Polymeric composition for ocular devices

ABSTRACT

Polymeric and co-polymeric compositions useful for preparing ophthalmic and ocular devices, such as implantable intraocular lenses (IOL) and contact lenses, and processes of forming the compositions and devices are provided. The disclosed polymeric or co-polymeric composition may include a curcuminoid compound as a UV-blocker, and is derived from a pre-polymerization mixture of monomers which comprises at least 50 weight percents acrylate monomers and exhibiting visible light transparency and ultraviolet light opacity. The disclosed co-polymeric composition may alternatively, or in addition, be derived from a pre-polymerization mixture of defined monomers.

RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.13/808,614, filed on Jan. 7, 2013, which is a National Phase of PCTPatent Application No. PCT/M2011/052976 having International Filing Dateof Jul. 5, 2011, which claims the benefit of India Patent ApplicationNos. 1938/MUM/2010 filed on Jul. 5, 2010, 2888/MUM/2010 filed on Oct.18, 2010 and 273/MUM/2011 filed on Feb. 1, 2011. The contents of theabove applications are all incorporated by reference as if fully setforth herein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to polymericand co-polymeric materials, and more particularly, but not exclusively,to polymeric and co-polymeric materials useful for preparing oculardevices such as intraocular, ophthalmic implants and contact lenses.

Light is an electromagnetic wave emitted by excited electrons; and assuch can reflect, refract and diffract. The human eye is a complexanatomical device, which evolved to interact with light and facilitatesinterpretation of shapes, colors, dimensions and relative position ofobjects by processing the light they reflect or emit. Similarly to acamera, the eye is able to refract light and produce a focused imagethat can stimulate neural responses and provide the ability to see. Theiris regulates the amount of light admitted to the interior of the eye,the cornea and the lens focus the light rays from an object being viewedonto the retina which transmits the image of the object to the brain viathe optic nerve. About 75% of the focusing is provided by the cornea,with the other 25% provided by the crystalline lens which may acquirevariable focal lengths.

The cornea is the most anterior structure of the eye. Since it has to betransparent to allow light to enter the eye, there are no blood vesselsin the cornea. The cornea is composed of collagen fibers packed togetherin an organized pattern, thereby providing the cornea its lighttransparent nature. The cornea has the highest concentration of nerveendings in the entire body, thus making it extremely sensitive to anykind of trauma. The front view of the cornea is of an aspheric shape,where the vertical dimension is smaller than the horizontal dimension byabout 1-2%. The anterior is typically about 11.7 mm in diameter.

The quality of vision depends on many factors including the size andshape of the eye, and the transparency of the cornea and lens. When ageor disease causes the lens to become less transparent, visiondeteriorates because of the diminished light which can be transmitted tothe retina. This deficiency in the lens of the eye is medically known asa cataract. An accepted treatment for this condition is a surgicalreplacement of the lens.

Corrective optic devices are used to correct refractive errors of theeye by modifying the effective focal length of the lens in order toalleviate the effects of conditions such as nearsightedness (myopia),farsightedness (hyperopia) or astigmatism. Another common condition inolder patients is presbyopia which is caused by the eye's crystallinelens losing transparency (cataract) and/or elasticity, progressivelyreducing the ability of the lens to accommodate, namely to focus onobjects close to the eye.

Corrective optic devices, also referred to herein as ophthalmic devices,include, for example, contact lenses and IOLs (intraocular lens, animplanted lens in the eye, usually replacing the existing crystallinelens because it has been clouded over by a cataract, or as a form ofrefractive surgery to change the eye's optical power), keratoprostheses,corneal rings, phakic lenses, aphakic lenses, capsular bag extensionrings, corneal inlays and corneal onlays. Corrective optic devices forrefractive errors also include eyeglasses, sunglasses or spectacles,comprising frames bearing lenses which are worn in front of the eyesnormally for vision correction, eye protection, or for protection fromUV rays.

Ophthalmic devices include cornea implants for artificial keratoplasty(keratoprostheses), cornea onlay lenses (contact lenses) or cornealinlay lenses or rings for correcting refractive errors, intraocularlenses for cataract surgery, phakic intraocular lenses in the posteriorchamber of eye and lenses for optical instruments. Generally, suchdevices operate accordion to the refraction and/or diffractionprinciples stemming from their shape and composition.

Contact lens is a corrective, cosmetic, or therapeutic lens usuallyplaced on and in contact with the cornea of the eye, hence the namecontact lens. Contact lenses usually serve the same corrective purposeas eyeglasses, but are typically soft, lightweight and virtuallyinvisible (some commercial lenses are tinted a faint blue to make themmore visible when immersed in cleaning and storage solutions). Somecosmetic lenses are deliberately colored to alter the appearance of theeye. Some contact lenses have a thin surface treatment which is aUV-absorbing coating; this helps to reduce UV damage to the eye'snatural lens. It has been estimated that 125 million people use contactlenses worldwide (2%).

Ophthalmic implants (also referred to herein as implantable ophthalmicdevices), such as intraocular lenses, differ from contact lenses mainlyby their permanent placement in the eye. Intraocular lenses (IOL), alsoknown as implantable contact lenses, are special small corrective lensessurgically implanted in the eye's posterior chamber behind the iris andin front of the lens to correct higher degrees of myopia and hyperopia.When age or disease causes the lens to become less transparent, visiondeteriorates because of the diminished light which can be transmitted tothe retina. This deficiency in the lens of the eye is medically known asa cataract. An accepted treatment for this condition is surgical removalof the lens and replacement of the lens function by an intraocular lens.Implantable ophthalmic devices can be surgically implanted into a livingcornea, or in other cases, are located in proximity to a damaged livingcornea. It is highly desirable, even essential, for the long termviability of such corrective lens structure onlays or implants, that thematerial constituting these devices be chemically and physically stableand capable of sustaining and possible filtering damaging radiation.Typically, this material is a polymer or co-polymer of some sort.

Over the years, numerous types of IOLs have been developed forcorrecting vision deficiencies. Generally, such lenses operate accordionto one or two basic optical principles: refraction and diffraction.

A typical optical device is manufactured from a polymeric composition,has a diameter of about 5-7 mm, and is supported in the eye by thespring force of flexible loops called haptics.

In general, the material used for ophthalmic implants is required to beand to remain stable in prolong exposure to wear and UV light, andremain transparent and substantially glistening-free and vacuoles-freefor extended periods of time at the physiological conditions of the eye,namely in contact with the eye's living tissue, tear enzymes and 37° C.A typical IOL is manufactured from polymethyl methacrylate, has adiameter of about 5-7 mm, and is supported in the eye by the springforce of flexible loops called haptics. Other materials are also used,and there are a variety of lens style and haptic designs.

Most contemporary contact optical devices, such as contact lenses andophthalmic implants which are used for small incision cataract surgery,require foldable materials like hydrophilic and hydrophobic acrylics andsilicones; however, hydrophilic acrylic/hydrogel suffers withincompatibly low refractive index (RI) and high posterior capsularopacification (PCO) rate. Other mechanical characteristics alsocontribute to this incompatibility, such as the springiness ofsilicon-based materials, which may result in corneal endothelium damageand/or rupture of capsular bag. Polymeric compositions such ashydrophobic acrylics are more desirable as these are typicallycharacterized by higher RI allowing smaller incision cataract surgery,minimal chances of PCO and controlled elasticity.

Thus, ophthalmic devices made from polymeric compositions should betransparent, flexible, deformable, glistening-free, vacuoles-free,contaminant-free (leachables), have low tackiness, low internalreflections, characterized by low stress generation or local burningwhile machining, and other handling and manufacturing problems.

WO 1994/011764 teaches foldable intraocular lenses made from polymericcompositions of high refractive index, comprising a copolymer includinga first constituent derived from a first monomeric component thehomopolymers of which have a refractive index of at least about 1.50, asecond constituent derived from a second monomeric component other thanthe first monomeric component the homopolymers of which have a glasstransition temperature of less than about 30° C., a third constituentderived from a crosslinking monomeric component in an amount effectiveto facilitate returning a deformed intraocular lens made of thesecompositions to its original shape, and a fourth constituent as ahydrophilic monomer. However WO 1994/011764 is silent with respect tothe superfluous unreacted monomer content which ultimately affectsglistening property of the lens and amount of undesired leachable(extractable) impurities.

WO 1999/007756 discloses high refractive index copolymer compositionssuitable for use in ophthalmic lenses, such as foldable intraocularlenses, consisting of conventional aromatic monomer and diacrylateoligomers such as epoxy acrylate, acrylated acrylics. WO 1999/007756 issilent with respect to several factors such as tackiness (stickiness,adhesiveness) of the resulting lenses resulting from monomers having alow Tg, internal reflection resulting from monomers having a high RI,and manufacturing process related internal stresses which results innon-linear heterogeneous mechanical/optical behavior of lenses.

U.S. Pat. No. 7,585,900 discloses soft, high refractive index, acrylicmaterials (polyethyl/methacrylate, PEA/PEMA) useful as intraocular lensmaterials, containing an aryl acrylic hydrophobic monomer as the singleprincipal device-forming monomer and a tack-reducing macromer additive(diacrylated polydimethyl siloxane, PDMS). However, PDMS requires customcomplex syntheses leading to higher production costs.

U.S. Pat. No. 5,331,073 discloses high refractive index polymericcompositions and foldable intraocular lenses made from suchcompositions. However, these acrylic-based polymeric compositionsinclude fluorine-containing monomers to rectify tackiness, which arecostly and present some biocompatibility issues.

U.S. Pat. No. 5,674,960 discloses PEA/PEMA-based high refractive indexpolymeric compositions, however, these compositions result in devicesthat suffer from internal reflection and persistent vacuoles in theophthalmic implants made therefrom.

EP 1030194 discloses polymeric compositions for soft, transparent andflexible intraocular lens, based on combinations of aryl acrylate andhydrophilic monomer, wherein the content of the hydroxyalkyl acrylatemonomer is at least 50%, rendering it too hydrophilic for compatiblecontact or implantable lenses.

U.S. Pat. No. 6,653,422 discloses soft, high refractive index, polymericcompositions for soft intraocular lenses, having an elongation of atleast 150%, constituting of aromatic monomers such as 4-phenyl butylacrylate, 3-benzyloxypropyl methacrylate in addition to PEA/PEMA.

U.S. Pat. No. 5,693,095 discloses polymeric compositions for foldableophthalmic lenses, comprising hydrophilic and hydrophobic aromaticacrylic component.

U.S. Patent Application Publication No. 2008139769 discloses(meth)acrylate copolymer compositions for soft intraocular lenses,obtained by copolymerization of a monomer mixture containing aromaticacrylic hydrophilic components along with hydrophobic components.

WO 2004/029675 teaches the formation of intraocular lenses through aprocess of pre-gel formation and in fused silica mold and a process ofcasting and extraction.

U.S. Pat. No. 7,304,117 teaches diphenyl azo-based reactive yellow dyesand a process for preparing polymers using the same in the manufacturingof ophthalmic devices, such as intraocular lenses, having blue lightabsorption properties. Said polymers are capable of blocking blue lightfrom reaching the retina of an eye implanted with the ophthalmic device,and thereby preventing potential damage to the retina.

U.S. Pat. No. 5,433,746 discloses polymer composition constitutingaromatic monomers like PEA/PEMA and the likes.

Implantable ophthalmic devices must overcome such issues as cytotoxicityand biocompatibility, which may arise from leachable (extractible)contaminants, hence all ophthalmic devices should be free from leachablecontaminants. To reduce these preexisting impurities, extraction stepsare typically carried out. WO 2004/029675, U.S. Patent ApplicationPublication Nos. 2005258096, 2004031275 and 2003116873 disclose suchextraction methods; however, such batch extraction methods suffer fromvarious process complexities and solvent issue.

U.S. Pat. No. 5,603,774 teaches reduction of the tackiness associatedwith certain such soft acrylic polymers useful for foldable intraocularlenses (IOLs), by plasma treatment of the polymer surface.

Additional background art includes U.S. Pat. Nos. 7,585,900, 5,693,095,5,290,892, 5,403,901, 5,433,746, 5,674,960, 5,716,403, 5,861,031,4,304,895 and 4,528,311, U.S. Patent Application Publication Nos.2003130460, 2009132039, 2008269884, 2003130460, 2008139769, 2008021129,2001014824, 2003116873 and 2005258096, WO 2001/018079, WO 2006/210438,WO 2006/187042, WO 1999/07756, WO 2009/137525, WO 2009/120511, WO20008/011566, WO 2008/011564, WO 2001/018079, WO 2001/018078, WO1999/007756, WO 2004/11764, WO 2004/029675, WO 2004/031275, WO2009/104516, WO 2006/095750, WO 2009/025399, JP 2003119226, KR20090047478, EP 1857477, CN101137684.

Light and oxygen induce degradation reactions in polymer-based devicesthat may not only modify them visually but also exert a detrimentalinfluence on numerous mechanical, physical and optical properties. Suchadverse effects can be minimized by use of light stabilizers which arechemical compounds able to interface with the physical and chemicalprocess of light induced degradation.

Radiation reaching the surface of the earth is composed of directsunlight and scattered light, and the ultraviolet (UV) part of theradiation spectrum is the part that is considered responsible forpolymer degradation. The Environmental Protection Agency (EPA or USEPA)designates sub-ranges of ultraviolet light as UVA (315-400 nm), UVB(280-315 nm) and UVC (10-280 nm). UVC and partly UVB rays are absorbedin the oxygen and ozone containing layer located in stratosphere,therefore only part of UVB and UVA radiation reaches the surface of theearth, and constitutes the main factor in aging for polymer-basedsystems. However, thinning of ozone layer is shifting UV spectralcomposition towards shorter wavelengths. It is accepted that UVradiation in the range of 280-380 nm, which corresponds to 420-320 kJ,is responsible for polymer degradation. This energy is sufficient tobreak C—C, C—H, C—O, C—Cl, C—N covalent bonds, hence signifies the needof using light stabilizers in ophthalmic devices which are exposed todirect or indirect sun-light.

UV light is also damaging to living cells, and among these, cell thatenable vision. Visible violet light contributes only 5% to scotopicvision (the monochromatic vision of the eye in dim light) but it isresponsible for up to 14% UV blue phototoxicity (a phenomenon known inlive-cell, where illuminating a fluorescent molecule or a fluorophore,causes the selective death of the cells that express this fluorophore).Ultraviolet radiation may also contribute to the development of oculardisorders such as cataract, ocular cancers, photokeratitis, maculardegeneration and corneal degenerative changes (e.g. pterygium, dropletclimatic keratopathy, pinguecula), retinitis pigmentosa, nightblindness, cystoid macular oedema, solar retinopathy (damage to theeye's retina, particularly the macula, from prolonged exposure to solarradiation), ocular melanomas and like damages.

Photokeratitis (also known as welder's flash or arc eye) is aninflammation of the cornea caused by a brief exposure to UV radiationLike sunburn, it may be painful and may create symptoms including redeyes, a foreign body sensation or gritty feeling in the eyes, extremesensitivity to light and excessive tearing. Scientific studies andresearch growing out of the U.S. space program have shown that exposureto small amounts of UV radiation over a period of many years mayincrease the chance of developing a cataract, and may cause damage tothe retina, the nerve-rich lining of the eye that is used for seeing.Retina damage is usually not reversible, and cumulative damage ofrepeated exposure may contribute to chronic eye disease, as well asincrease the risk of developing skin cancer around the eyelids.Long-term exposure to UV light is also a risk factor in the developmentof pterygium (a growth that invades the corner of the eyes) andpinguecula (a yellowish, slightly raised lesion that forms on thesurface tissue of the white part of the eye).

Ultraviolet light (higher energy with respect to visible light) can bedamaging to the light receptor cells. With a few exceptions (e.g.,snakes, placental mammals), most organisms avoid these effects by havingabsorbent oil droplets around their cone cells. The alternative,developed by organisms that had lost these oil droplets in the course ofevolution, is to make the lens impervious to UV light, precluding thepossibility of UV light being detected, as it does not reach the retina.In the human and other animal eye, UV light is absorbed by moleculesknown as chromophores, which are present in the eye cells and tissues.Chromophores absorb light energy from the various wavelengths atdifferent rates; a pattern known as absorption spectrum. Furthermore,natural chromophores found in the eye block UV light by fluorescence.

Transparent polymer-based ophthalmic devices are most sensitive to UVlight, including visible violet light (400-440 nm). Most of theophthalmic device research and manufacturing companies incorporatesynthetic UV-blockers/absorbers (also referred to herein as lightstabilizing additives or light stabilizers) in their ophthalmic devices.The primary function of light stabilizers is to protect the substancefrom the long-term degradation effects from light, most frequentlyultraviolet light. Different UV stabilizers are utilized depending uponthe substrate, intended functional life, and sensitivity to UVdegradation. UV stabilizers, such as hydroxyphenyl-benzotriazole,hydroxyphenyl-triazine and benzophenone-based light stabilizers, act byabsorbing the UV radiation and preventing the formation of, orscavenging, free radicals. Depending upon substitution, the UVabsorption spectrum is changed to match the application, while theirconcentrations typically range from 0.05% to 5% by weight of thepolymer.

Unlike naturally occurring chromophores, synthetic dyes used asUV-blockers for incorporation in transparent polymer-based ophthalmicdevices typically do not show any kind of fluorescence, hence are lesseffective in blocking UV radiation than naturally occurring UV-blockers.Furthermore, synthesis of organic UV-blockers/absorbers intended forincorporation into transparent polymer-based ophthalmic devices involvescomplex, multi-step and costly manufacturing process, which limits thechoice of the polymer to great extent. In addition to their productionlimits, synthetic light stabilizing additives may lack biocompatibilityto some extent, and as such may cause the development ofhypersensitivity of the epithelium cell layers after prolonged contacttherewith, and may cause impairment of scotopic vision.

Moreover, in the case of implantable ophthalmic devices, the thicknessof a typical device is required to be kept at a minimum for the sake ofsmaller incisions. In addition, the concentration of any potentiallyharmful UV-blockers must be kept at the lowest. Thus, since there is adirect link between the UV-blocking effect and the amount of UV-blockerin the path of the light, UV-blockers are required to have a largecross-section for interaction with the incoming UV radiation.UV-blockers with a relatively low cross-section are less suitable foruse in transparent polymer-based ophthalmic devices since they require along light-path and/or a high concentration in the transparentpolymer-based ophthalmic device in order to block UV effectively.

U.S. Pat. Nos. 5,234,990 and 5,578,676 teach compositions for forminganti-reflective layers for DUV microlithographic processes, whichinclude polysulfone and polyurea polymers that possess inherent lightabsorbing properties at deep ultraviolet wavelengths. These compositionsare applied to a substrate to form an anti-reflective coating, andthereafter a photoresist material that is compatible with theanti-reflective coating is applied. These polymers are said to includean additive such as 4,4,-bis(N,N-dimethylamino)benzophenone,7-diethylamino-4-methylcoumarian, curcumin, 3-aminopropyltriethoxysilaneor (3-glycidoxypropyl)trimethoxysilane. These polymers are also said tobe opaque, hence are not suitable for use in ophthalmic devices.

U.S. Pat. No. 7,304,117 teaches novel azo-based reactive yellow dyes anda process for manufacturing polymers, using the same in themanufacturing of ophthalmic devices, such as intraocular lenses, havingblue light absorption properties. Said polymers are capable of blockingblue light from reaching the retina of an eye implanted with theophthalmic device, and thereby preventing potential damage to theretina.

U.S. Patent Application Publication No. 20070204412 teaches transparentsilicone polymers and elastomers colored by curcumin and/or a derivativethereof.

SUMMARY OF THE INVENTION

The present invention, in some embodiments thereof, relates to polymericand/or co-polymeric compositions useful for forming intraocular,ophthalmic implants, contact lenses and other ophthalmic and oculardevices.

The present inventors have devised the following compositions:

i) an improved hydrophobic co-polymeric composition made from a uniquecombination of constituents which confer a unique combination ofbeneficial optical, chemical and mechanical attributes;

ii) a polymeric or co-polymeric composition, based on at least 50 weightpercents acrylate monomers, which includes a curcuminoid compound thatserves as a natural and highly effective UV-blocker; and

iii) the improved hydrophobic co-polymeric composition described in (i)above, further comprising a curcuminoid compound as a UV-blocker.

Hence, according to an aspect of some embodiments of the presentinvention, there is provided a co-polymeric composition which includes apolymeric backbone composed of a plurality of backbone units covalentlylinked to one another, the backbone units being derived from apre-polymerization mixture of monomers which includes:

a first aromatic acrylate monomer, characterized as forming a firsthomopolymer having a refractive index that ranges from 1.50 to 1.53;

a second aromatic acrylate monomer, characterized as forming a secondhomopolymer having a Tg lower by a range of 2° C. to 30° C. than a Tg ofthe first homopolymer;

a third monomer, characterized as forming a third homopolymer having aTg lower than 35° C.;

a fourth monomer, characterized as forming a fourth homopolymer which iscapable of absorbing water to at least 20% of the total weight of thefourth homopolymer; and

a fifth monomer, being a crosslinking monomer,

wherein:

a concentration of the first aromatic acrylate monomer ranges from 50%to 60% of the total weight of the composition;

a concentration of the second aromatic acrylate monomer ranges from 15%to 20% of the total weight of the composition;

a concentration of the third monomer ranges from 10% to 15% of the totalweight of the composition;

a concentration of the fourth monomer ranges from 5% to 10% of the totalweight of the composition;

a concentration of the fifth monomer ranges from 2% to 5% of the totalweight of the composition; and

the composition being formulated for ophthalmic application.

In some embodiments, the hydrophobic co-polymeric composition presentedherein further includes an ultraviolet absorbing compound.

In some embodiments, the hydrophobic co-polymeric composition furtherincludes at least one curcuminoid compound incorporated therein orthereon.

In some embodiments, a concentration of the first aromatic acrylatemonomer ranges from 52% to 59% of the total weight of the composition;the concentration of the second aromatic acrylate monomer ranges from15% to 19% of the total weight of the composition; the concentration ofthe third monomer ranges from 11% to 15% of the total weight of thecomposition; the concentration of the fourth monomer ranges from 7% to9% of the total weight of the composition; and the concentration of thefifth monomer ranges from 2% to 3.5% of the total weight of thecomposition.

In some embodiments, the first aromatic monomer is selected from thegroup consisting of 2-phenoxyethyl acrylate, 2-phenoxy ethylmethacrylate, 2-benzyloxy ethyl acrylate, 2-benzyloxy ethyl methacrylateand combinations thereof.

In some embodiments, the second aromatic monomer is selected from thegroup consisting of 2-phenylethyl acrylate, benzyl acrylate, cyclohexylacrylate, 2-chlorophenyl acrylate, 4-methyl benzyl acrylate,2,4,6-tribromophenyl acrylate, pentabromophenyl acrylate and anycombinations thereof.

In some embodiments, the third monomer is selected from the groupconsisting of cellosolve methacrylate, methoxy ethyl acrylate,polyethylene glycol monomethacrylate, 1-dihydroxyperflurobutylmethacrylate, 2,5-dibromopropyl methacrylate, hexyl methacrylate,glycerol monomethacrylate, trifluroethyl methacrylate, butylmethacrylate, n-ocyl/isooctyl methacrylate, n-decyl/isodecylmethacrylate, ethyl methacrylate, ethylene triglycol methacrylate, butyldiglycol methacrylate, methoxy polyethylene glycol 350 methhacrylate,methoxy polyethylene glycol 500 methhacrylate, methoxy polyethyleneglycol 1000 methhacrylate, methoxy polyethylene glycol 2000methhacrylate. methoxy polyethylene glycol 5000 methhacrylate,polypropylene glycon methacrylate, ethoxytriglycol methacrylate,2-ethoxyethoxy ethyl methacrylate, methoxy triethyleglycol methacrylate,phenoxy polyethylene glycol monomethacrylate and any combinationsthereof.

In some embodiments, the forth monomer is selected from the groupconsisting of hydroxyl ethyl methacrylate, glycerol monomethacrylate,ethylene triglycol methacrylate, butyl diglycol methacrylate, methoxypolyethylene glycol 350 methhacrylate, methoxy polyethylene glycol 500methhacrylate, methoxy polyethylene glycol 1000 methhacrylate, methoxypolyethylene glycol 2000 methhacrylate, methoxy polyethylene glycol 5000methhacrylate, polypropylene glycon methacrylate, ethoxytriglycolmethacrylate, methoxy triethyleglycol methacrylate, phenoxy polyethyleneglycol monomethacrylate and any combinations thereof.

In some embodiments, the fifth monomer is selected from the groupconsisting of ethylene glycol dimethacrylate, 1,4-butane dioldiacrylate, glycerol dimethacrylate, allyl methacrylate, 1,6 heaxanediol diacrylate, 1,4-butanediol dimethacrylate, 1,6-hexane dioldimethacrylate and any combinations thereof.

In some embodiments, the mixture further includes a free radicalpolymerization initiator.

In some embodiments, the initiator is a low temperature dissociationinitiator.

In some embodiments, the initiator is selected from the group consistingof dicetyl peroxydicarbonate, tert-butyl peroxypivalate, diisobutyrylperoxide, dimyristyl peroxydicarbonate, 1,1,3,3-tetramethylbutylperoxypivalate, tert-butyl peroxyneoheptanoate,di(2-neodecanoylperoxy-isopropyl)benzene, cumylperoxy-neodecanoate,1,1,3,3-tetramethylbutylperoxy-neodecanoate, t-butylperoxy-neodecanoate,t-butylperoxy-neoheptanoate and any combinations thereof.

In some embodiments, the ultraviolet absorbing compound is selected fromthe group consisting of a benzophenone, 2-hydroxybenzophenone,2-(2-hydroxyphenyl)benzotriazole, 2-acryloxyethoxy hydroxylbenzophenone,phenol-2-(5-chloro-2H-benozotriazol-2-yl)-6-(1,1-)dimethyl-4-methyl,4-benzoyl-3-hydroxyphenyl-2-methacrylate,2-[4-(2h-1,2,3-benzotriazol2-yl)-3-hydroxyphenoxy]ethyl-2-methacrylateand any combinations thereof.

According to another aspect of some embodiments of the presentinvention, there is provided a composition which includes a polymer orco-polymer and a curcuminoid compound incorporated in or on the polymeror co-polymer, the polymer or co-polymer being derived from apre-polymerization mixture of monomers which includes at least 50 weightpercents acrylate monomers.

In some embodiments of the composition having the curcuminoid compoundincorporated therein or thereon, the acrylate monomer is selected fromthe group consisting of an acrylate, a methacrylate, an aryl acrylateand an aryl methacrylate.

In some embodiments of the composition having the curcuminoid compoundincorporated therein or thereon as a natural UV-blocker, the compositionis a hydrophobic co-polymeric composition being derived from apre-polymerization mixture of monomers includes:

a first aromatic acrylate monomer, characterized as forming a firsthomopolymer having a refractive index that ranges from 1.50 to 1.53;

a second aromatic acrylate monomer, characterized as forming a secondhomopolymer having a Tg lower by a range of 2° C. to 30° C. than a Tg ofthe first homopolymer;

a third monomer, characterized as forming a third homopolymer having aTg lower than 35° C.;

a fourth monomer, characterized as forming a fourth homopolymer which iscapable of absorbing water to at least 20% of the total weight of thefourth homopolymer; and

a fifth monomer, being a crosslinking monomer,

wherein:

a concentration of the first aromatic acrylate monomer ranges from 50%to 60% of the total weight of the composition;

a concentration of the second aromatic acrylate monomer ranges from 15%to 20% of the total weight of the composition;

a concentration of the third monomer ranges from 10% to 15% of the totalweight of the composition;

a concentration of the fourth monomer ranges from 5% to 10% of the totalweight of the composition; and

a concentration of the fifth monomer ranges from 2% to 5% of the totalweight of the composition, as described herein.

According to another aspect of some embodiments of the presentinvention, there is provided a co-polymeric composition which includes apolymeric backbone composed of a plurality of backbone units covalentlylinked to one another and a curcuminoid compound incorporated in or onthe composition, the backbone units being derived from apre-polymerization mixture of monomers which includes:

a first aromatic acrylate monomer, characterized as forming a firsthomopolymer having a refractive index that ranges from 1.50 to 1.53; asecond aromatic acrylate monomer, characterized as forming a secondhomopolymer having a Tg lower by a range of 2° C. to 30° C. than a Tg ofthe first homopolymer; a third monomer, characterized as forming a thirdhomopolymer having a Tg lower than 35° C.; a fourth monomer,characterized as forming a fourth homopolymer which is capable ofabsorbing water to at least 20% of the total weight of the fourthhomopolymer; and a fifth monomer, being a crosslinking monomer, wherein:

a concentration of the first aromatic acrylate monomer ranges from 50%to 60% of the total weight of the composition; a concentration of thesecond aromatic acrylate monomer ranges from 15% to 20% of the totalweight of the composition; a concentration of the third monomer rangesfrom 10% to 15% of the total weight of the composition; a concentrationof the fourth monomer ranges from 5% to 10% of the total weight of thecomposition; and a concentration of the fifth monomer ranges from 2% to5% of the total weight of the composition, as described herein, thecomposition being formulated for ophthalmic application.

In some embodiments of any of the compositions presented herein, themixture further includes a curing agent.

In some embodiments of any of the compositions presented herein, thecuring agent is selected from the group consisting of a peroxy catalyst,an oxide catalyst, tert-butyl peroxy-2-ethylhexanoate,2,4,6-trimethylbenzoyldiphenylphosphine oxide and any combinationsthereof.

In some embodiments, any of the compositions presented herein furtherincludes an additive selected from the group consisting of a dye, ayellow dye/blue light blocker, a coating material, a heparin coatingagent, a photochromic coating agent, a light-stabilizer, apharmaceutical agent, a cell receptor functional group, a protein group,a viscosity agent, a diluent and any combination thereof.

In some embodiments, the compositions presented herein are having avisible light transmission of at least 97% of incident visible light.

In some embodiments, the compositions presented herein are having arefractive index of at least 1.53.

In some embodiments, the compositions presented herein are having looppull force mechanical strength of at least 60 grams.

In some embodiments, the compositions presented herein are characterizedby a glass transition temperature not higher than 5° C.

In some embodiments, the compositions presented herein are characterizedby Shore A hardness that ranges from 77 to 80.

In some embodiments, the compositions presented herein are having anunfolding time of less than 6 seconds.

In some embodiments, the compositions presented herein are characterizedby having essentially no internal reflections.

In some embodiments, the compositions presented herein are characterizedby having essentially no vacuoles and/or perceivable glistening.

In some embodiments, the compositions presented herein are having aleachable content of less than 0.6%.

In some embodiments, the compositions presented herein are essentiallytack free.

In some embodiments of the compositions presented herein which include acurcuminoid compound, the concentration of the curcuminoid compoundranges from 0.0002 weight percentage to 1 weight percentage of the totalweight of the composition.

In some embodiments of the compositions presented herein, theconcentration of the curcuminoid compound decreases by less than 0.0001weight percentage when the composition is subjected to a solventextraction.

In some embodiments, the curcuminoid compound containing compositionspresented herein are substantially transparent to light at a wavelengthranging from about 400 to about 800 nm.

In some embodiments, the curcuminoid compound containing compositionspresented herein are substantially opaque to light at a wavelengthranging from about 190 to about 440.

In some embodiments of the compositions presented herein which include acurcuminoid compound, the curcuminoid compound is selected from thegroup consisting of curcumin, bisdemethoxycurcumin,monodemethoxycurcumin and tetrahydroxycurcumin.

In some embodiments, any of the compositions presented herein isidentified for use in the manufacturing of an ophthalmic or oculardevice.

In some embodiments, the ophthalmic or ocular device is selected fromthe group consisting of an intraocular lens (IOL), a contact lens, animplantable ocular device, a keratoprosthesis, a phakic lens, an aphakiclens, a corneal ring, a capsular bag extension ring, a corneal inlay anda corneal onlay.

According to another aspect of some embodiments of the presentinvention, there is provided a process of preparing the compositions aspresented herein, which is effected by:

admixing the pre-polymerization mixture of monomers and a free radicalpolymerization initiator;

heating the pre-polymerization mixture to 40° C. while stirring until aviscosity reach 120 cps at 25° C.;

degassing the pre-polymerization mixture so as remove volatile residues;

admixing an additional amount of the initiator into thepre-polymerization mixture so as to obtain a reaction mixture;

admixing a curing agent into the reaction mixture;

casting the reaction mixture into a mold;

exposing the reaction mixture to curing conditions, to thereby obtainthe composition.

In some embodiments, the process presented herein further includes,prior to the casting, filtering the reaction mixture.

In some embodiments, the process presented herein further includes,subsequent to the exposing the reaction mixture to the curingconditions, subjecting the composition to a multiple extraction.

In some embodiments, the process presented herein further includes,subsequent to the exposing the reaction mixture to the curingconditions, exposing the composition to a treatment selected from thegroup consisting of a plasma treatment, a surface fluorination, a bulkfluorination, a hydrophilic coating, an electron beam irradiation, ahigh energy UV irradiation, a energy intensive irradiation, a internalwetting agent and any combination thereof.

In some embodiments of the process presented herein, the multipleextraction includes releasing the composition from the mold; andsequentially immersing the composition in a series of solvent baths tothereby extract unreacted contaminants.

In some embodiments, the process presented herein further includes,subsequent to the exposing the reaction mixture to the curingconditions, polishing and/or machining the composition so as to obtain afinal form.

According to another aspect of some embodiments of the presentinvention, there is provided an ophthalmic or ocular device which isformed substantially from the compositions presented herein.

In some embodiments, the device is selected from the group consisting ofan intraocular lens (IOL), a contact lens, an implantable ocular device,a keratoprosthesis, a phakic lens, an aphakic lens, a corneal ring, acapsular bag extension ring, a corneal inlay and a corneal onlay.

In some embodiments, the device is identified for use in the treatmentof an optical distortion, retinopathy, a retinal detachment, anocclusion, proliferative retinopathy; proliferative vitreoretinopathy,diabetic retinopathy, a degenerative disease and an age-related maculardegeneration.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings and images.With specific reference now to the drawings and images in detail, it isstressed that the particulars shown are by way of example and forpurposes of illustrative discussion of embodiments of the invention. Inthis regard, the description taken with the drawings and images makesapparent to those skilled in the art how embodiments of the inventionmay be practiced.

In the drawings:

FIG. 1 presents the UV-Vis absorption spectra of a sample of curcuminafter purification on a preparative silica gel column at 25° C., using amixture of chloroform and ethyl acetate (9:1 ratio);

FIGS. 2A-B present the UV/Vis transmission and absorption spectra asmeasured from slice samples of a rod-shaped object prepared from acurcumin/POEMA/CHMA/BDDA polymerization mixture, an exemplarycomposition according to some embodiments of the present invention,after mild washing and drying (FIG. 2A) and after Soxhlet extraction for3 hours in toluene (FIG. 2B);

FIGS. 3A-D present the UV/Vis transmission and absorption spectra, asmeasured after Soxhlet extraction and drying, obtained from transparentslices having curcumin at a final content of 0.005 weight percents (FIG.3A), PDPMA at a final content of 0.005 weight percents (FIG. 3B),curcumin at a final content of 0.025 weight percents (FIG. 3C), andPDPMA at a final content of 0.025 weight percents (FIG. 3D); and

FIGS. 4A-D present the UV/Vis absorption spectra, as collected from lensprepared with curcumin at 0.025 weight percentage, before extraction(FIG. 4A), from the same lens after extraction (FIG. 4B), from lensprepared with curcumin at 0.05 weight percentage, before extraction(FIG. 4C), and from the latter lens after extraction (FIG. 4D).

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to polymericand co-polymeric materials, and more particularly, but not exclusively,to polymeric and co-polymeric materials useful for preparing oculardevices such as intraocular, ophthalmic implants and contact lenses.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details set forth in the following description orexemplified by the Examples. The invention is capable of otherembodiments or of being practiced or carried out in various ways.

Shape and composition of optical devices determine their interactionwith light. While the shape of an optical device such as a lens mainlycontrols refractive and diffractive aspects, the composition mainlycontrols absorptive, refractive and reflective aspects. Lighttransmissive polymeric materials have been used for decades to constructoptical devices as corrective measures for refractive errors and otherconditions of failing eye sight and vision. Such materials have beenfound suitable for lenses due to the ease of forming various complex andprecise shapes therefrom, using casting, molding, machining, polishingand various combinations of these industrial techniques, and due to therelative chemical stability of such polymeric compositions under variousconditions.

Yet, presently known polymeric compositions used in the manufacturing ofophthalmic and ocular devices, and particularly implantable devices,suffer from a variety of shortcomings, including, for example,bio-incompatibility, leachable contaminants, degradation inphysiological conditions, UV vulnerability, incompatible refractiveindex, internal reflections, tackiness, glistening, vacuoles, high costof materials and manufacturing complexities.

As discussed hereinabove, presently known UV-blocking and lightstabilizing additives and synthetic chromophores, used in polymericcompositions for ophthalmic and ocular devices, suffer from one or moredrawbacks, including biocompatibility, physical, mechanical and chemicalstability, and manufacturing factors (e.g., cost and complex syntheses).

The present inventors have sought a comprehensive solution to a group ofproblems associated with ophthalmic and ocular devices made frompolymeric and/or co-polymeric compositions, including biocompatible andUV-light stabilized materials. The present inventors furthercontemplated the unique UV-stabilizing effect of curcuminoid compoundsfor devising a UV-stabilized polymeric-based multifocal ophthalmicdevice.

In general, ophthalmic and ocular devices differ from spectacles(eye-glasses) and other optical devices, by being designed to be indirect contact with the living tissue of the eye or its immediatesurroundings. The devices which come in such direct contact are requiredto be biocompatible, as discussed herein, as well as to have certainphysical properties with respect to their mechanical reshapability andreformability, flexibility, water-absorption capacity, and the likes.Implantable devices differ from non-implantable devices mainly by theirmode of use and administration as well as their term of use, namely thedevices that require a surgical procedure in order to be put in placeare typically referred to as implantable. Implantable ophthalmic andocular devices are expected to last longer and thus the requirements fortheir stability and compatibility in all aspects are much higher.

The term “bio-compatible”, as used in reference to polymeric andco-polymeric compositions as presented herein, refers to the non-toxicand benign effect that the composition has on a living tissue (e.g., aneye or a portion or a component thereof) when in contact therewith.

The term “chemo-compatible”, as used in reference to polymeric andco-polymeric compositions as presented herein, refers to the long-termnon-leachability of unreacted components and diluents, non-degradabilityand overall long-term chemical stability of the composition when incontact with a living tissue in the eye and exposed to ambient light.

The term “physico-compatible”, as used in reference to polymeric andco-polymeric compositions as presented herein, refers to the opticalproperties of the compositions in terms of refractive index, internalreflections, light transmission and/or absorbance, and other propertiesrelating to light-matter interaction.

As used herein, the phrase “ophthalmic and ocular device”, refers todevices that reside in or on the eye. These devices can provide opticalcorrection, lens replacement, wound care, drug delivery, diagnosticfunctionality, cosmetic enhancement or effect or a combination of theseproperties. The phrase “ophthalmic and ocular device”, as used herein,encompasses, but is not limited to, soft contact lenses, hard contactlenses, intraocular lenses (IOLs), implantable lenses, keratoprostheses,phakic and aphakic lenses, corneal overlay and inlay lenses, ocularinserts, corneal rings, capsular bag extension rings, and opticalinserts.

The ophthalmic and ocular device of the present embodiments can befabricated in any technique known in the art. A formed (molded) andcured polymeric or co-polymeric composition can be unprocessed orpartially post-processed by machining, in which case polishing and masssubtraction determines the final shape and finish of the device, asknown in the art.

Improved Polymeric or Co-Polymeric Compositions for OphthalmicApplications:

According to an aspect of some embodiments of the present inventionthere are provided polymeric or co-polymeric compositions which aresuitable for use in ophthalmic applications.

In some embodiments of the present invention, the polymeric orco-polymeric compositions presented herein are derived from apre-polymerization mixture of monomers. In polymeric compositions, themonomers in the mixture are the same whereby in co-polymericcompositions several different classes of monomers are used. As in anypolymer, the polymeric or co-polymeric composition is based on pluralityof polymeric backbones, each of which consists of a plurality ofbackbone units which are covalently attached to one another, and each ofthe backbone units comprises a plurality of building-blocks orpolymerized monomeric units. Hence, the composition, which is theoutcome of polymerizing a pre-polymerization mixture of monomers, can becharacterized and defined at the chemical and physical property level,in terms of the pre-polymeric mixture, namely its constituents prior topolymerization.

The monomers which are put into the pre-polymerization mixture are stillunreacted (not yet polymerized) and are regarded as the startingmaterials for the compositions presented herein. In the case of aco-polymeric composition, each of the monomers, identified andclassified into classes, can be characterized by chemical and physicalproperties exhibited by the corresponding homopolymer which is derivedfrom each of the individual monomer in the class. Hence, co-polymericcompositions as presented herein can be characterized by the monomerclass which it is derived from, as well as the relative amount-ratiosbetween each monomer class in the pre-polymerization mixture.

As used herein, the term “monomer” is used to describe a constituent ofthe pre-polymerization mixture which affords, upon polymerization, thepolymeric or co-polymeric compositions presented herein. It is notedherein that while some of the constituents of the pre-polymerizationmixture participate in the polymerization process as reactants whichform covalent bonds with other constituents in the mixture during thepolymerization process, some may not react with other constituents in acovalent-bond-forming reaction, but become embedded or incorporatedwithin the matrix of the polymeric or co-polymeric composition, as willbe discussed hereinbelow.

According to some embodiments of the present invention, apre-polymerization mixture as described herein may include any of themonomers as described herein, as a starting material, in its monomericform, or, alternatively, as a polymeric building block, which typicallyhas a relatively low average molecular weight of about less than 2000Daltons (as measured via gel permeation chromatography refractive indexdetection). According to other embodiments of the present invention, thestarting material can include dimmers of a monomer (two monomeric unitsor building blocks) and in some cases be a short oligomer of buildingblocks, including oligomers made from more than one type of monomericunit. Short oligomers are commonly referred to in the art as “blocks”.

It is noted that a polymeric or co-polymeric composition of the presentembodiments is compatible for use in the eyes and is optically clear andsuitable for use as material of construction of ophthalmic and oculardevice. By optically clear it is meant that the composition isessentially transparent to visible light, as described and definedherein.

The term “transparent”, used herein in the optical sense, describes thephysical property of a substance to allow light to pass (transmit)therethrough. The term “transparent” is used herein as the opposite tothe term “opaque”, and it is not used to refer to translucency ortranslucidity (partial transparency). Hence, in the context of thepresent embodiments, a transparent substance is clear, and exhibitspellucidity or diaphaneity. The term transparent does not necessarilyrefer to other manifestations of light-matter interactions such asdiffraction, refraction or dispersion. Accordingly, the term “opaque”,used herein in the optical sense, describes the physical property of asubstance to block (absorb) light from passing (transmitting)therethrough.

The properties of transparency and opacity may be wavelength dependent,meaning that the same substance may be transparent with respect to lightof a certain range of wavelengths, while at the same time be opaque withrespect to light of another range of wavelengths, hence acting like awavelength-selective filter of light. In the context of the presentembodiments, a substantially transparent composition allows at least 98%of the light intensity of a given range of wavelength to passtherethrough (a maximal loss of 2% of the light's intensity), while asubstantially opaque composition reflects, scatters or absorbs more than98% of the incoming light of a given range of wavelength, allowing lessthan 2% of the light to pass therethrough. Alternatively, transparencyis defined as transmission of 95% of the light intensity of a givenrange of wavelength.

Visible light, as defined by the visibility of a typical human eye, ischaracterized by a wavelength ranging from 390 nm to 750 nm. Accordingto some embodiments of the present invention, the composition for makingthe ophthalmic devices presented herein is characterized by beingsubstantially transmissive (transparent) to visible light.

Hydrophobic Co-Polymeric Compositions for Ophthalmic Applications:

According to an aspect of some embodiments of the present invention,there are provided co-polymeric compositions which are suitable for usein ophthalmic applications.

The co-polymeric compositions presented herein are based on fivematrix-forming constituents as well as other ingredients such ascatalyst, UV-stabilizer/UV-blocker and high energy visible blue lightstabilizer. The compositions may further comprise colorant/dyeadditives, leachable agents (drugs) and the likes.

The co-polymeric composition presented herein typically andadvantageously exhibits relatively high refractive indexes when in itsfinal form and fully hydrated. The refractive index of the final andfully hydrated co-polymeric composition presented herein, is typicallygreater than about 1.5, more typically greater than about 1.51, stillmore typically greater than about 1.52 and even possibly greater than1.53 or even 1.54, wherein the refractive index of the fully hydratedcomposition is measured at 25° C. in accordance with ASTM D 542-00(2006).

Hence, according to some embodiments of the present invention, there isprovided a co-polymeric composition, being formulated for ophthalmicapplication,

the composition being derived from a mixture of monomers that include:

a first aromatic acrylate (aryl acrylate) monomer characterized asforming, upon polymerization thereof, a first homopolymer which exhibitsa refractive index that ranges from 1.50 to 1.53;

a second aromatic acrylate (aryl acrylate) monomer characterized asforming, upon polymerization thereof, a second homopolymer, whichexhibits a Tg (glass transition temperature) lower than the Tg of thehomopolymer derived from the first monomer by a range of 2 to 30 degreescentigrade;

a third monomer characterized as forming, upon polymerization thereof, athird homopolymer, which exhibit a Tg lower than 35° C. or lower than37° C.;

a fourth monomer characterized as forming, upon polymerization thereof,a fourth homopolymer, which exhibit a capacity to absorb water to atleast 20% of its dry weight; and

a fifth monomer serving a crosslinking agent,

wherein:

a concentration of the first aromatic acrylate monomer ranges from 50%to 60% of the total weight of the composition;

a concentration of the second aromatic acrylate monomer ranges from 15%to 20% of the total weight of the composition;

a concentration of the third monomer ranges from 10% to 15% of the totalweight of the composition;

a concentration of the fourth monomer ranges from 5% to 10% of the totalweight of the composition; and

a concentration of the fifth monomer ranges from 2% to 5% of the totalweight of the composition.

It is noted that the co-polymeric compositions presented herein, whichare formed from a number of monomer classes, referred to herein as afirst, second, third, fourth and fifth monomers, can include a varietyof different monomers of each class, namely one or any number ofmonomers mentioned within the class of monomers corresponding to thefirst, second, third, fourth or fifth monomer.

Unless otherwise stated, the percentages (e.g., weight percentages) ofthe constituents of the co-polymeric composition presented herein aredenoted as weight percentages of the starting material with respect tothe total weight of the pre-polymerizable mixture.

According to some embodiments of the present invention, the co-polymericcomposition presented herein contains less than 75% in total of arylacrylate monomers.

The major component of the co-polymeric composition is neverthelessbased on aryl acrylate, as opposed to mixtures of aryl methacrylate andaryl acrylate which are known in the related art, which is less suitablefor producing an ophthalmic and ocular device as presented herein.

One disadvantage of using aryl acrylate and aryl methacrylate/acrylatein more than 80% concentration is the occurrence of internal reflectionsand glare which may appear in the device made from such co-polymericcomposition. This disadvantage is mitigated by strictly controlling thecontent of any aryl-containing monomer.

In general, every monomer adds from its associated property toco-polymeric composition, and when all property adds up in aprerequisite proportion, they form a co-polymeric composition suitingthe desired application.

The fifth monomer (class) is a crosslinking agent, as definedhereinbelow, interchangeably referred to herein as a crosslinker, whichis characterized according to its capacity to alter the strength,rigidity and consistency of the co-polymeric composition presentedherein. Thus, the crosslinking monomer (the fifth monomer) is acomponent having an effect on controlling flexibility of the obtainedmaterial for a soft embodiment of composition presented herein, givingthe desired mechanical strength, improving capability of deformationrecovery, and increasing co-polymerizable property with components forpolymerization. Co-polymeric compositions which are not cross-linked maydeteriorate rapidly as polymer chains are loosely held and increasingthe possibility of getting extracted out under soxhlation extraction(gel content), resulting into loss of strength, loss of shape recoveryand higher occurrence of vacuoles. The crosslinker is also theconstituent that leads to an increase in the molecular weight of thecomposition (size of an average contiguous chain) by tethering chains toone-another. The molecular weight of the composition has a direct effecton the glistening, mechanical properties, refractive index and manyother mechanical and optical properties of the composition andsubsequently a device made therefrom.

The first monomer (class) is an aromatic-containing (or aryl-containing)acrylate type monomer (hence, a first aromatic monomer) which ischaracterized as forming, upon polymerization thereof, a firsthomopolymer having a refractive index between 1.50-1.53 (a criterion forselecting the first monomer). As a constituent of the co-polymericcompositions presented herein, the first monomer can include one or moremonomer structures, namely different monomers wherein each satisfies atleast the aforementioned criterion.

Acrylate monomers constitute a family which is a type of vinyl monomers,or esters which contain a vinyl group, namely two carbon atomsdouble-bonded to each other, directly attached to the carbonyl carbon ofa carboxyl group, as illustrated in Scheme 1 below.

The term “methacrylate” refers to an acrylate monomer having a methylgroup at position R₂ in Scheme 1 above.

The phrase “aromatic acrylate”, as used herein, refers to an acrylateester having an aromatic substituent attached to the carbonyl, denotedR₄ in Scheme 1 above. Accordingly, the phrase “aromatic methacrylate”refers to a monomer as illustrated in Scheme 1 above, wherein R₂ is amethyl group and R₄ is an aryl or a heteroaryl group.

An “aryl” group refers to an all-carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, naphthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted.

A “heteroaryl” group refers to a monocyclic or fused ring (i.e., ringswhich share an adjacent pair of atoms) group having in the ring(s) oneor more atoms, such as, for example, nitrogen, oxygen and sulfur and, inaddition, having a completely conjugated pi-electron system. Examples,without limitation, of heteroaryl groups include pyrrole, furane,thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine,quinoline, isoquinoline and purine. The heteroaryl group may besubstituted or unsubstituted.

Without being bound by a particular theory, the rational behind usingaryl ether acrylate monomers is their relatively flexible result-polymercompared to straight chain aryl alkyl methacrylate which adds to greaterdeforming ability into lens matrix without significantly compromising onrefractive index and hydrophobicity.

Exemplary monomers that are suitable for use as a first monomeraccording to embodiments of the invention include 2-phenoxyethylacrylate, 2-phenoxy ethyl methacrylate, 2-benzyloxy ethyl acrylate,2-benzyloxy ethyl methacrylate and combinations thereof.

Other non-limiting examples of the first aromatic acrylate monomeraccording to some embodiments of the present invention, include2-ethylphenoxy methacrylate; 2-ethylphenoxy acrylate; 2-ethylthiophenylmethacrylate; 2-ethylthiophenyl acrylate; 2-ethylaminophenylmethacrylate; 2-ethylaminophenyl acrylate; phenyl methacrylate; phenylacrylate; benzyl methacrylate; benzyl acrylate; 2-phenylethylmethacrylate; 2-phenylethyl acrylate; 3-phenylpropyl methacrylate;3-phenylpropyl acrylate; 4-phenylbutyl methacrylate; 4-phenylbutylacrylate; 4-methylphenyl methacrylate; 4-methylphenyl acrylate;4-methylbenzyl methacrylate; 4-methylbenzyl acrylate;2-2-methylphenylethyl methacrylate; 2-2-methylphenylethyl acrylate;2-3-methylphenylethyl methacrylate; 2-3-methylphenylethyl acrylate;24-methylphenylethyl methacrylate; 2-4-methylphenylethyl acrylate;2-(4-propylphenyl)ethyl methacrylate; 2-(4-propylphenyl)ethyl acrylate;2-(4-(1-methylethyl)phenyl)ethyl methacrylate;2-(4-(1-methylethyl)phenyl)ethyl acrylate; 2-(4-methoxyphenyl)ethylmethacrylate; 2-(4-methoxyphenyl)ethyl acrylate;2-(4-cyclohexylphenyl)ethyl methacrylate; 2-(4-cyclohexylphenyl)ethylacrylate; 2-(2-chlorophenyl)ethyl methacrylate; 2-(2-chlorophenyl)ethylacrylate; 2-(3-chlorophenyl)ethyl methacrylate; 2-(3-chlorophenyl)ethylacrylate; 2-(4-chlorophenyl)ethyl methacrylate; 2-(4-chlorophenyl)ethylacrylate; 2-(4-bromophenyl)ethyl methacrylate; 2-(4-bromophenyl)ethylacrylate; 2-(3-phenylphenyl)ethyl methacrylate; 2-(3-phenylphenyl)ethylacrylate; 2-(4-phenylphenyl)ethyl methacrylate; 2-(4-phenylphenyl)ethylacrylate; 2-(4-benzylphenyl)ethyl methacrylate; and2-(4-benzylphenyl)ethyl acrylate, and the like.

Additional examples for suitable first monomers include naphthylacrylates, dicyclopentyloxy acrylates, dicyclopentyl acrylates,nonylphenoxy polyethyleneglycol 200 acrylates, nonylphenoxypolyethyleneglycol 400 acrylates, alkoxylated phenol acrylates,2-methacryloyloxyethyl 2-hydroxy propyl phthalates, 2-acryloxyethyl-2-hydroxy ethyl phthalates, 2-hydroxy-3-phenoxy propyl acrylates,neopentyl glycol benzoate acrylates and the likes.

According to some embodiments of the present invention, theconcentration of the first monomer ranges from 52% to 59% of the totalweight of the composition.

The second monomer (class) is another aromatic acrylate monomercharacterized as forming, upon polymerization thereof, a secondhomopolymer having a Tg lower than the Tg of the first homopolymer,which is derived from the first monomer, by 2 to 30 degrees centigrade(° C.).

Non-crystalline polymeric solids are referred to as amorphous materials(atoms or molecules are not arranged in a lattice that repeatsperiodically in space). For all amorphous solids, whether glasses,organic polymers, and even metals (although having a lattice), Tg is thecritical temperature that separates their glassy and rubbery behaviors.A glass is defined as a material that has no long-range atomic ormolecular order and is below the temperature at which a rearrangement ofits atoms or molecules can occur. On the other hand, a rubber is anon-crystalline solid whose atoms or molecules can undergorearrangement. If a material is at a temperature below its Tg,large-scale molecular motion is not possible because the material isessentially frozen. If it is at a temperature above its Tg, molecularmotion on the scale of its repeat unit (such as 50-mer in a polymer)takes place, allowing it to be “soft” or “rubbery”. It is noted that theterm “Tg” is applies herein to non-crystalline solids, which are mostlyeither “glasses” or “rubbers”.

Hence, the phrases “glass transition temperature” or “rubber-glasstransition temperature”, as used herein in the context of polymers,refers to the temperature at which the Gibbs free energy is such thatthe activation energy for the cooperative movement of about 50 elements(50-mer) of the polymer is exceeded compared to a reference point,meaning that molecular chains are able to slide past each other when aforce is applied. A glass transition temperature of a non-crystallinematerial, such as a polymer, is the critical temperature at which thematerial changes its behavior from being “glassy” to being “rubbery”,while lowering the temperature across the Tg affords vitrification.“Glassy” in this context means hard and brittle (and thereforerelatively easy to break), while “rubbery” means elastic and flexibleand can absorb kinetic energy without shuttering.

According to some embodiments of the present invention, the chemicalstructure of the second monomer can follow the same chemical rationalcharacterizing the first monomer, with the difference that the secondmonomer is selected according to the Tg characterizing the secondhomopolymer being lower than the Tg of the first homopolymer by 2-30° C.

The choice of a second aromatic monomer according to embodiments of theinvention include, depends on the choice of the first monomer asdifference in relative Tg is the criterion for selecting the secondmonomer. Therefore, there is much overlap in the range of options of thefirst and the second monomers.

Exemplary monomers that are suitable for use as a second aromaticmonomer according to embodiments of the invention include, but are notlimited to 2-phenylethyl acrylate, benzyl acrylate, 4-methyl benzylacrylate, 2,4,6-tribromophenyl acrylate, pentabromophenyl acrylate andany combinations thereof.

According to some embodiments of the present invention, theconcentration of the second monomer ranges from 15% to 19% of the totalweight of the composition.

It is noted herein that some ophthalmic and ocular devices, andparticularly implantable devices, are required to avoid posteriorcapsular opacification (PCO) after cataract replacement surgery. Thisadverse effect is related also to the tackiness of the composition. Tocontrol tackiness, suitable monomers are selected for the co-polymericcomposition, while not compromising the refractive index of theresulting composition. Hence, the co-polymeric composition presentedherein exhibits tackiness to some degree so as to avoid PCO, andtherefore tackiness should be high enough to reduce PCO, and low enoughso as not to hinder handling.

Thus, the first monomer is meant to be restricted to the above-mentionedrange, since the first monomer is characterized by a relatively higherTg which makes the resulting polymer less tacky than the polymerresulting from the second monomer. These formulation restrictions conferrelatively low tackiness without compromising the target refractiveindex. At the same time, the reason for keeping a high Tg monomer(higher than a low Tg monomer), is to confer mechanical strength to thecomposition, which increases due to higher crystallinity impartmentthereto.

It is further noted herein that according to some embodiments of thepresent invention, a relatively high Tg aryl monomer is used as a majorconstituent, while the prior art teaches the use of lower Tg arylmonomer as a major part of the composition. For example, U.S. Pat. No.5,290,892 teaches the use of 2-phenyl ethyl acrylate in higher amountcompared to 2-phenyl ethyl methacrylate, while methacrylate compoundshave higher Tg compared to corresponding acrylate compound. Together itforms at least 80% of the composition taught in U.S. Pat. No. 5,290,892.

The third monomer (class) is characterized as forming, uponpolymerization thereof, a third homopolymer having a Tg lower than 37°C. The third monomer is the component which has a notable effect on theflexibility of the obtained composition, conferring softness to thedevice, and improving its capability to recover from deformation. Thecapacity to recover quickly from deformation (reformability) is requiredby an ophthalmic device when applied to the eye after folding and whilefollowing the shape shifts of the eye.

Exemplary monomers that are suitable for use as a third monomeraccording to embodiments of the invention include, but are not limitedto, cellosolve methacrylate, methoxy ethyl acrylate, polyethylene glycolmonomethacrylate, 1-dihydroxyperflurobutyl methacrylate,2,5-dibromopropyl methacrylate, hexyl methacrylate, glycerolmonomethacrylate, trifluroethyl methacrylate, butyl methacrylate,n-ocyl/isooctyl methacrylate, n-decyl/isodecyl methacrylate, ethylmethacrylate, ethylene triglycol methacrylate, butyl diglycolmethacrylate, methoxy polyethylene glycol 350 methhacrylate, methoxypolyethylene glycol 500 methhacrylate, methoxy polyethylene glycol 1000methhacrylate, methoxy polyethylene glycol 2000 methhacrylate. methoxypolyethylene glycol 5000 methhacrylate, polypropylene glyconmethacrylate, ethoxytriglycol methacrylate, 2-ethoxyethoxy ethylmethacrylate, methoxy triethyleglycol methacrylate, phenoxy polyethyleneglycol monomethacrylate and any combinations thereof.

According to some embodiments of the present invention, theconcentration of the third monomer ranges from 11% to 15% of the totalweight of the composition.

It is noted herein that use of aryl ether acrylate and aryl alkylacrylate, such as 2-phenoxy ethyl acrylate and 2-phenyl ethyl acrylate,gives superior results over the use of methacrylate and acrylate of samependant group as described in the art.

Methacrylate groups are known to increase the rigidity of the resultantpolymer, since methacrylate compounds exhibit side chain crystallizationthereby increasing rigidity. According to some embodiments of thepresent invention, it is suggested herein to introduce high Tg arylether acrylate monomer which also imparts flexibility to theco-polymeric composition, enabling 20D IOL delivery even through a sub 2mm incision in a wound assisted surgical technique. An additionaladvantage of using aryl ether acrylate is its relatively less tackynature compared to aryl alkyl methacrylate.

By using lesser amount of aryl acrylate monomer, polymer of relativelylow refractive index is prepared to avoid glare/internal reflectionproblem at the same time, refractive index is maintained to a level thatit would enable the lens to go through sub 2 mm incision.

For increasing strength and reformability, monomers like methoxy ethylmethcaylate are used. Its Tg is lower than 37° C. and it formsrelatively hydrophobic polymer than conventional 2-ethoxy ethylmethacrylate. In general, in the pendant ether group, odd number ofmethylene (CH₂) gives optimal results. Examples include methoxy ethylacrylate, propoxy ethyl acrylate, pentoxy ethyl acrylate and the likes.

The fourth monomer (class) is a hydrophilic monomer which ischaracterized as forming, upon polymerization thereof, a fourthhomopolymer exhibiting a capacity to absorb water to at least 20% of itsdry weight.

Water content of the homopolymer made from hydrophilic monomer shouldabsorb enough so as to conform to the requirement of ophthalmic devicessuch as contact lenses and IOLs. After extraction of the leachables fromthe formulation, a process that is discussed hereinbelow, vacuoles mayform in the product. Hence, all hydrophobic polymeric compositionsexhibit vacuoles and some water absorption. When ophthalmic device comesin a contact with water or another aqueous medium, these media wouldtend to concentrate at the vacuoles.

Prime purpose of using a hydrophilic monomer is to uniformly dispersethe water in the matrix. After putting the ophthalmic device inphysiological medium like normal saline or highly pure water, thesevacuoles give rise to white spots. To overcome this problem, hydrophilicmonomer would disperse water uniformly rather than allowing water toconcentrate in voids and vacuoles. This uniform dispersion gives rise toclear and spotless lenses. It also helps to increase the strength of thematrix and to control its tackiness.

Some commonly available hydrophilic monomer absorbs more than 20% of thetotal weight of their corresponding homopolymer. If the required watercontent in the composition should be kept bellow 20%, other monomers canbe selected so as to counter-effect the absorption of water.

The forth monomer is also effective to reduce tackiness of theco-polymeric composition presented here, as well as to improve itsmechanical properties, as well as to uniformly disperse water moleculesthroughout the matrix at a wide temperature change.

As used herein, the phrase “hydrophilic monomer” refers to compoundswhich produce hydrogel-forming homopolymers, namely homopolymers whichbecome associated with substantial amounts of water (for example, atleast 20% based on the weight of the dry homopolymer), and whichphysically swell as a result of such association.

Exemplary fourth monomers include, without limitation, alkoxy alkyl(meth)acrylate; N-vinyl pyrrolidone; hydroxyalkyl acrylates andhydroxyalkyl methacrylates, such as 2-hydroxyethyl acrylate,2-hydroxyethyl methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropylmethacrylate, 4-hydroxybutyl acrylate, 4-hydroxybutyl methacrylate,2,3-dihydroxypropyl acrylate, 2,3-dihydroxypropyl methacrylate and thelike; acrylamide; N-alkyl acrylamides such as N-methyl acrylamide,N-ethyl acrylamide, N-propyl acrylamide, N-butyl acrylamide and thelike; acrylic acid; methacrylic acid; and the like and mixtures thereof.

Additional exemplary monomers that are suitable for use as a fourthmonomer according to embodiments of the invention include, but are notlimited to, hydroxyl ethyl methacrylate, glycerol monomethacrylate,ethylene triglycol methacrylate, butyl diglycol methacrylate, methoxypolyethylene glycol 350 methhacrylate, methoxy polyethylene glycol 500methhacrylate, methoxy polyethylene glycol 1000 methhacrylate, methoxypolyethylene glycol 2000 methhacrylate, methoxy polyethylene glycol 5000methhacrylate, polypropylene glycon methacrylate, ethoxytriglycolmethacrylate, methoxy triethyleglycol methacrylate, phenoxy polyethyleneglycol monomethacrylate and any combinations thereof.

According to some embodiments of the present invention, theconcentration of the fourth monomer ranges from 7% to 9% of the totalweight of the composition.

As used herein, the phrase “cross-linking monomer” refers to a substancethat promotes or regulates intermolecular covalent, ionic, hydrophobicor other form of bonding between polymer chains, linking them togetherto create a network of chains which result in a more rigid structure.Crosslinking monomers, according to some embodiments of the presentinvention, contain at least two reactive groups that are reactivetowards a variety of groups, including double bonds, sulfhydryls andamines, and create chemical bonds between two or more polymer molecules.Crosslinking monomers include homo-bifunctional crosslinking monomersthat have two identical reactive end groups, and hetero-bifunctionalcrosslinking monomers which have two different reactive end groups.These two classes of crosslinking monomers differ primarily in thechemical reaction which is used to effect the crosslinking step, whereinhomo-bifunctional crosslinking monomers will require a one stepreaction, and hetero-bifunctional crosslinking monomers will require twosteps to effect the same. While homo-bifunctional crosslinking monomershave the tendency to result in self-conjugation, polymerization, andintracellular cross-linking, hetero-bifunctional agents allow morecontrolled two step reactions, which minimize undesirable intramolecularcross reaction and polymerization. Crosslinking monomers are furthercharacterized by different spacer arm lengths. A crosslinking monomerwith a longer spacer arm may be used where two target groups are furtherapart and when more flexibility is desired.

Exemplary crosslinking monomers include, without limitation, butanedioldi(meth)acrylate, ethylene glycol di(meth)acrylate, diethylene glycoldi(meth)acrylate, triethylene glycol di(meth)acrylate, propylene glycoldi(meth)acrylate, dipropylene glycol di(meth)acrylate, diallyl fumarate,allyl (meth)acrylate, vinyl (meth)acrylate, trimethylolpropanetri(meth)acrylate, methacryloyloxyethyl (meth)acrylate, divinylbenzene,diallyl phthalate, diallyl adipate, triallyl diisocyanate,α-methylene-N-vinylpyrrolidone, 4-vinylbenzyl(meth)acrylate,3-vinylbenzyl (meth)acrylate,2,2-bis((meth)acryloyloxyphenyl)hexafluoropropane,2,2-bis((meth)acryloyloxyphenyl)propane, 1,4-bis(2-(meth)acryloyloxyhexafluoroisopropyl)benzene,1,3-bis(2-(meth)acryloyloxyhexafluoroisopropyl)benzene, 1,2-bis(2-(meth)acryloyloxyhexafluoroisopropyl)benzene, 1,4-bis(2-(meth)acryloyloxyisopropyl)benzene, 1,3-bis(2-(meth) acryloyloxyisopropyl)benzene, 1,2-bis(2-(meth) acryloyloxyisopropyl)benzene, and the like.These crosslinking monomers can be used solely or in a combination useof two or more thereof. Among those, ethylene glycol dimethacrylate andbutanediol diacrylate are widely use effect controllable flexibility,desired mechanical strength, improved capability of deformationrecovery, and increased co-polymerizable property.

Additional exemplary monomers that are suitable for use as a fifthmonomer according to embodiments of the invention include, but are notlimited to ethylene glycol dimethacrylate, 1,4-butane diol diacrylate,glycerol dimethacrylate, allyl methacrylate, 1,6 heaxane dioldiacrylate, 1,4-butanediol dimethacrylate, 1,6-hexane dioldimethacrylate and any combinations thereof.

According to some embodiments of the present invention, theconcentration of the fifth monomer ranges from 2% to 3.5% of the totalweight of the composition.

The amount of the fifth monomer (crosslinker) depends on selection ofthe prior monomers. It is added to have an optimal shape recovery, tolessen the extractables and reduce glistening. An excess amount mayincrease glistening of composition after introduction into physiologicalmedium. Lesser amount may result into loss of strength, higherextractables (more vacuoles) and slower shape recovery.

In addition, the co-polymeric compositions presented herein can includea variety of additional or alternative ingredients, feature additivesand the likes. Examples include, without limitation, UV blockers, dyes,light-stabilizers, coating materials, pharmaceuticals (therapeuticagents), cell receptor functional groups, protein groups, viscosityagents (e.g., thickeners or thinners), diluents, combinations thereof orthe like.

As discussed hereinabove, each and every constituent in the co-polymericcompositions presented herein, as well as their relative proportion inthe making thereof, contribute to the wide range of requirements andnecessary characteristics of these compositions.

For example, according to some embodiments of the present invention, thecompositions presented herein exhibit visible light transmission of atleast 97% of incident visible light, as determined according to ASTM D1003 standard and/or ISO 11979-2:2000 standard.

In addition, the compositions presented herein exhibit a refractiveindex of at least 1.53, as determined according to the ASTM D542-00(2006) standard.

In addition, or alternatively, according to some embodiments of thepresent invention, the co-polymeric compositions presented hereinexhibit a loop pull force mechanical strength of at least 60 grams, atleast 50 grams or at least 40 grams, as determined according to the ISO11979-3:2006 standard.

In addition, or alternatively, the co-polymeric compositions presentedherein are further characterized by a glass transition temperature nothigher than 5° C., not higher than 10° C. or not higher than 15° C., asdetermined according to the ASTM D3418-03:2000 standard.

In addition, or alternatively, Shore A hardness exhibited by theco-polymeric compositions according to some embodiments of the presentinvention, ranges from 77 to 80, as determined according to the ASTMD2240:2000 standard.

In addition, or alternatively, according to some embodiments of thepresent invention, the co-polymeric compositions presented hereinexhibit an unfolding time of less than 6 seconds for full recovery oforiginal shape injected through a sub 2 mm cartridge at roomtemperature. Such requirement is important when a device made of thecomposition is placed in position by inserting it under leaving tissuewith a narrow gauge cartridge (sub 2 mm).

The co-polymeric composition according to some embodiments of thepresent invention, is characterized by having essentially no internalreflections, and further have essentially no vacuoles and/or perceivableglistening as determined by visual inspection at a magnification of 50×.

One of the requirements of an ophthalmic or ocular device, involvingleachable content, is clearly met by the co-polymeric compositionspresented herein, which have a leachable content of less than 0.6%, asdetermined according to the ISO 11979-5:2006 and/or the ISO 11979-5:2006standards.

According to some embodiments of the present invention, the co-polymericcompositions presented herein are essentially tack-free, as determinedaccording to the ASTM D 3654 standard.

The co-polymeric compositions as described herein can also be referredto as hydrophobic co-polymeric compositions.

An ophthalmic or ocular device made from the co-polymeric compositionspresented herein can also be referred to as a hydrophobic diffractiveophthalmic device and can be, for example, a hydrophobic diffractiveIOL.

According to some embodiments of the present invention, the co-polymericcompositions presented herein further includes a radiation-resistantcompound, which is typically referred to as a UV-blocker agent oradditive, UV-light stabilizer and/or UV-absorbent agent. The terms“UV-blocker” and “UV-stabilizer”, and grammatical diversions andinflections thereof, are used herein interchangeably, since stabilizinga polymeric composition against the degradation caused by UV-light stemsalso from the capacity to block UV-light by the composition.

The role of protection from UV damages, both to the eye (protect lightsensitive retina) and the co-polymeric composition itself, can be takenby one type of UV-blocker or a combination of several differentcompounds, some embedded and some co-polymerized with the composition.The UV-blocker can thus be a polymerizable constituent, which presentsadvantages in terms of leachability of the agent, and it can be anembedded constituent, namely incorporated consistently in the matrix ofthe polymeric composition so as not to leach out.

It is noted herein that UV-protection is particularly desirable forophthalmic or ocular devices, which may be located within the eye forextended periods of time (e.g., greater than 6 months, a year, severalyears or more) as opposed to, for example, disposable contact lenses. Assuch, it is highly desirable for these types of devices to exhibitlonger term resistance to degradation caused by radiation exposure.

An ultraviolet absorbing material (UV-blocker additive or agent) can beany natural or synthetic compound which absorbs ultraviolet light, i.e.,light having a wavelength shorter than about 400 nm, but does not absorbany substantial amount of visible light. A natural UV-blocker can be acurcuminoid compound, as defined and discussed herein. The ultravioletabsorbing compound is incorporated into the monomer mixture and isembedded or entrapped in the polymer matrix when the monomer mixture ispolymerized. According to some embodiments of the present invention, theUV-blocker provide a transmission cut-off above a wavelength of 385 andtypically provide cut-off in the short wavelength visible (410-430 nm)region of the electromagnetic spectrum. Such chromophores can thenprovide desired protection to the human eye and/or the device materialfrom UV radiation (<400 nm). Suitable UV-blockers can also be referredto as UV/short wavelength visible light absorbers, dye or chromophores.

Unless otherwise specified, “cut-off” means the wavelength at whichlight transmission does not exceed 1%. “1% cut-off” means the wavelengthat which light transmission does not exceed 1%. “10% cut-off” means thewavelength at which light transmission does not exceed 10%.

Typical ultraviolet absorbing compounds, based on syntheticchromophores, include substituted benzophenones, such as2-hydroxybenzophenone, and 2-(2-hydroxyphenyl)benzotriazoles. Accordingto some embodiments of the present invention, the ultraviolet absorbingcompound may be co-polymerizable with the monomers and is thereby firmlyembedded in the polymer matrix. In this way possible leaching of theultraviolet absorbing compound out of the lens and into the interior ofthe eye is minimized. Suitable co-polymerizable ultraviolet absorbingcompounds include substituted 2-hydroxybenzophenones as disclosed in,for example, U.S. Pat. No. 4,304,895 (incorporated by reference as fullyset forth herein) and 2-hydroxy-5-acryloxyphenyl-2H-benzotriazolesdisclosed in U.S. Pat. No. 4,528,311 (incorporated by reference as fullyset forth herein). Alternatively, the ultraviolet absorbing compound is2-(3′-methallyl-2′-hydroxy-5′methyl phenyl) benzotriazole.

Other synthetic ultraviolet absorbing compounds includephenol-2-(5-chloro-2H-benozotriazol-2-yl)-6-(1,1-)dimethyl-4-methyl(Tinuvin® 326), 4-benzoyl-3-hydroxyphenyl-2-methacrylate,2-[4-(2h-1,2,3-benzotriazol2-yl)-3-hydroxyphenoxy]ethyl-2-methacrylateand combination thereof.

Optic devices based on co-polymeric compositions may also comprise apolymerizable or embedded yellow dye that attenuates medium- tolong-wavelength (430-500 nm) blue light. Such dyes and other usefulchromophores are described in U.S. Pat. No. 7,691,918, which is fullyincorporated herein for all purposes.

Yellow dye gives a yellowish tint to lens; natural lens tends to getyellow as age of patient progresses. Yellow tinted artificial lens givesthe elderly patient the appearance of a natural lens. The yellow dyealso provides protection from visible blue light which may lead to agerelated macular degeneration.

Presently known UV-blocking additives and synthetic chromophores, usedin polymeric compositions for ophthalmic and ocular devices, may sufferfrom one or more drawbacks, including biocompatibility, physical,mechanical and chemical stability, and manufacturing factors (e.g., costand complex syntheses).

Polymeric or Co-Polymeric Compositions Containing Curcuminoid as aNatural UV-Blocker:

According some embodiments of the present invention, the co-polymericcomposition described hereinabove (also referred to herein as aco-polymer or a hydrophobic co-polymeric composition), further includesa natural UV-blocker in the form of a curcuminoid compound incorporatedin or on the co-polymeric composition.

In general, curcuminoids can be utilized effectively as UV-blockers inany polymeric or co-polymeric composition useful in ophthalmicapplication.

Hence, according to another aspect of the present invention, there isprovided a polymeric or co-polymeric composition which includes at leastone curcuminoid compound, as presented herein, incorporated in or on thecomposition as a mean of providing UV-light stabilization, wherein thepolymeric or co-polymeric composition is derived from apre-polymerization mixture of monomers.

According to some embodiments of the present invention, polymeric orco-polymeric compositions in which a curcuminoid compound incorporatedtherein or thereon, is made from a pre-polymerization mixture ofmonomers which includes at least 50 percents acrylate monomers.

According to some embodiments pertaining to this aspect of the presentinvention, the acrylate monomer is selected from the group consisting ofan acrylate, a methacrylate, an aryl acrylate and an aryl methacrylate.

As demonstrated in the Examples section that follows, one exemplaryco-polymer which includes a curcuminoid compound can be formed from oneor more monomers such as, but not limited to, 2-phenoxy ethylmethacrylate (POEMA), cyclohexyl acrylate (CHMA) and 1,4-butane dioldiacrylate (BDDA). An exemplary composition, according to someembodiments of the present invention, is formed, for example, from apre-polymerization mixture containing 50-70% 2-phenoxy ethylmethacrylate (POEMA), 20-50% cyclohexyl acrylate (CHMA) and 1-5%1,4-butane diol diacrylate (BDDA), and 0.001-0.5% curcuminoid compound,each measured by dry weight percentages of the total dry weight of thepre-polymerization mixture. Other constituents may also be included inminor amounts, such as a catalyst (a polymerization initiator agent),cross-linking monomers, colorant/dye additives and the likes.

Alternatively, a co-polymeric composition in or on which a curcuminoidcompound is incorporated, can be made from a pre-polymerization mixturewhich includes the aforementioned five constituents (monomer classes),as described hereinabove. Therefore, some of the above-describedembodiments relate to a co-polymeric composition which includes apolymeric backbone composed of a plurality of backbone units covalentlylinked to one another, which is derived from a pre-polymerizationmixture of monomers having a unique formulations as presented herein,and further includes at least one curcuminoid compound, as presentedherein, incorporated in or on the composition as a mean to provideUV-light stabilization.

Hence, according to another aspect of the present invention, there isprovided a co-polymeric composition formulated for ophthalmicapplications (the hydrophobic co-polymeric compositions as describedherein), which includes a polymeric backbone composed of a plurality ofbackbone units covalently linked to one another, which is derived from apre-polymerization mixture of monomers as described hereinabove, andwhich further comprises a curcuminoid compound incorporated therein orthereon, as described herein.

Such a composition, which includes a curcuminoid compound in aparticular co-polymeric composition, can be prepared essentially asdescribed herein, while the curcuminoid compound is added to thepre-polymerized mixture prior to curing and thereby allowed to beincorporated into the co-polymeric composition.

The term “incorporated”, as used herein, refers to the physical state ofone substance in a composition containing other substances. In thecontext of some embodiments of the present invention, an incorporatedcurcuminoid compound is incorporated within a polymeric or co-polymericcomposition as described herein such that the curcuminoid compound is atleast partially surrounded by the polymeric or co-polymeric compositionand entrapped thereby.

In some embodiments, the incorporated curcuminoid compound isdistributed within the polymeric or co-polymeric composition in auniform and sustainable form, and is enclosed in the surrounding mass.

According to some embodiments of the present invention, the curcuminoidcompound incorporated within the polymeric or co-polymeric compositionis not covalently attached to one or more constituents of the polymericor co-polymeric composition. In some embodiments, the curcuminoidcompound interacts with the polymeric or co-polymeric composition viaphysical interactions, such as, for example, entanglement, absorption,adsorption and/or entrapment, and not via chemical interactions such ascovalent, ionic, or hydrogen bonds.

Curcuminoids constitute a versatile group of chromophore-containingsubstances, which can be selected by their light absorption propertiesto suit a particular application.

In general, curcuminoids are polyphenols characterized by a pronouncedyellow color, and most of the naturally occurring curcuminoids,including curcumin itself, have been recognized as generally safe forhuman consumption and suitable for pharmaceutical purposes.

The term “curcuminoid”, as used herein, is used to collectively describecurcumin, as well as derivatized curcumin compounds. Derivatizedcurcumin compounds have a curcumin backbone structure, and optionallyhave one or more different chemical groups (substituents) attached atvarious positions of the curcumin backbone structure. A derivatizedcurcumin compound may differ from curcumin by chemical and physicalcharacteristics, such as solubility, reactivity, light interaction andthe likes, as a result of its substituents.

Curcuminoid compounds according to some embodiments of the presentinvention, can be collectively represented by General Formula I:

According to some embodiments of the present invention, each of D₁ andD₂ is individually selected from the group consisting of O, N, S orC(aryl), whereas D₁ and D₂ may be connected directly or via a connectingatom to form a conjugated ring (aryl, heteroaryl etc.); and wherein eachof R₁-R₁₅ is individually selected from the group consisting of alkyl,alkoxy and hydroxy.

An “aryl” group refers to an all-carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, naphthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted.

A “heteroaryl” group refers to a monocyclic or fused ring (i.e., ringswhich share an adjacent pair of atoms) group having in the ring(s) oneor more atoms, such as, for example, nitrogen, oxygen and sulfur and, inaddition, having a completely conjugated pi-electron system. Examples,without limitation, of heteroaryl groups include pyrrole, furane,thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine,quinoline, isoquinoline and purine. The heteroaryl group may besubstituted or unsubstituted.

The curcuminoid compound utilized in embodiments of the presentinvention can be a naturally-occurring curcuminoid or a syntheticallyprepared curcuminoid, with naturally-occurring curcuminoids being moredesirable.

Exemplary curcuminoid compounds that are suitable for use in the contextof some embodiments of the present invention include, but are notlimited to, curcumin (illustrated in the scheme below),bisdemethoxycurcumin, monodemethoxycurcumin and tetrahydroxycurcumin,which are all natural curcuminoids found in plants such as the curcumaspecies.

(1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-6-heptadiene-3,5-dione(Curcumin)

The naturally occurring curcuminoids differ from one another in both thenumber and position of the methoxy groups, and all exhibit a keto-enoltautomerism in the mid-section of the chromophore chain. Thesecurcuminoids differ in their light absorbing and free radical scavengingproperties. All of the naturally-occurring curcuminoids may serve asefficient UV-blockers and/or stabilizers, in the context of embodimentsof the present invention. For instance, some natural curcuminoid sourcescontain tetrahydroxycurcumin (THC), which is a colorless compound, whichcan be used as a UV stabilizer in applications where yellow color is notrequired or desired.

THC is a suitable curcuminoid compound, according to some embodiments ofthe present invention, in applications where yellowish tint is to beavoided.

Curcuminoid compounds can be extracted as naturally occurring substancesor be prepared synthetically, and can be used as mixtures thereof or asisolated species. Curcuminoid compounds which are also encompassed bythe present embodiments are disclosed in, for example, U.S. Pat. No.3,479,345, U.S. Patent Application Publication Nos. 20030153512,20060276536, 20070060644, 20070204412, 20080200478, 20100010232,20100048901, 20100048901 and 20100087527, all of which are incorporatedherein by reference as if fully set forth herein.

It is noted herein that the benefits of incorporating a curcuminoidcompound in ophthalmic and ocular devices applies to any polymeric orco-polymeric composition comprising the same. Thus, an ophthalmic orocular device, according to some embodiments of the present invention,can be made from any suitable polymeric or co-polymeric composition asknown in the art, and the curcuminoid compound can be added to thepre-polymerized mixture of the composition before curing, or appliedthereon after curing, as described herein.

In some embodiments, the curcuminoid compound is incorporated into thecomposition as described herein.

As can be seen in the Examples section that follows, the presentinventors have successfully incorporated curcumin in an exemplaryco-polymeric composition which is suitable for use in ophthalmic andocular devices, and were able to obtain a desirable level oftransparency towards visible light and at the same time opacity withrespect to ultraviolet light, using a relatively low concentration ofcurcumin.

The present inventors have thus demonstrated that naturally occurring(natural) compounds such as curcuminoids, which are generally recognizedas safe for human consumption and somatic use, can be used with polymersor co-polymers, such as substantially acrylate-based polymers, to formlasting compositions with suitable UV/blue light blocking and UV-lightstabilization properties. The present inventors have shown that usingcurcuminoids in ophthalmic and ocular devices as blue/UV light blockersmay overcome the limitations and possible impairments associated by theuse of synthetic compounds such as diphenyl-azo-based,benzotriazole-based and benzophenone-based UV-blockers and the like.

It has further demonstrated by the present inventors that curcuminoidscan be used effectively even at low concentration in a polymeric orco-polymeric composition, relative to the concentration required forbenzophenone-based and benzotriazole-based UV-blockers, in order toachieve comparable effective UV-blocking. A low concentration of theUV-blockers not only affects the cost of the resulting product but alsoaffects the visual clarity of the product and its final dimensions.Furthermore, the proven UV-blocking effectiveness of curcuminoids wouldmake it highly suitable in the manufacturing of ophthalmic and oculardevices.

Thus, relatively low concentrations of the curcuminoids are sufficientto exhibit the desired activity. Hence, according to some embodiments ofthe present invention, the concentration of the curcuminoid compound inthe composition ranges from 0.0002 weight percentage to 1 weightpercentage or from 0.001 weight percentage to 0.5 weight percentage ofthe total weight of the composition. Any value lower than 1 weightpercent is contemplated, hence any value lower than 0.9, 0.8, 0.7, 0.6,0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.001 and any value lower than 0.0005weight percent is contemplated as well.

It has been further demonstrated that curcuminoids, unlike many knownsynthetic phenol-containing UV-blockers, do not inhibit or retard therate and/or degree of polymerization, when added to thepre-polymerization mixture.

The use of compounds of the curcuminoid family allows selecting acompound with certain optical characteristics, such as, for example, aparticular light-absorption range and a particular color or lackthereof.

Without being bound by any particular theory, it is suggested that thetransparency of the polymeric or co-polymeric composition is maintainedupon incorporating curcumin therein due to the relatively lowconcentration of the embedded curcumin. Such low concentration issufficient due to the effective UV-absorption characteristics ofcurcuminoids and the surprising finding that curcuminoids do not leachout of polymers or co-polymers derived from pre-polymerization mixtureshaving at least 50 percents acrylic monomers.

As further demonstrated in the Examples section that follows, curcuminwas found to be incorporated firmly and consistently in an exemplarypolymeric composition, as confirmed by the stability of itsconcentration in the tested composition before and after the testedcomposition was subjected to extended cycles of extraction in organicsolvents which are known to dissolve curcumin.

As discussed hereinbelow, substances that can leach (be extracted) outof a matrix may cause several adverse effects, such as harming thebiological environment (tissue) surrounding the matrix, and reducing theeffectiveness of the composition in, for example, blocking UV light.Hence, the characteristic behavior of the curcuminoid in polymeric orco-polymeric compositions can be referred to as low leachability (fromthe term “leachable”) with respect to the matrix constituents and withrespect to the curcuminoid compound, and can be defined in terms ofcomparison of concentrations before and after an extraction process, asthis process is discussed hereinbelow.

Low leachability is significant when a substance is used in implantabledevices, since in such devices, long-term performance is desired.

The process by which the incorporation of the curcuminoid compound isevaluated is also referred to as the extraction step of unreactedcomponents and diluents (UCDs) from the cured composition, which isdiscussed in detail hereinbelow, and exemplified in the Example sectionthat follows below.

According to some embodiments of the present invention, there is noperceivable difference in the concentration of the curcuminoid compoundafter the extraction process for removal of UCDs. Hence, according tosome embodiments of the present invention, any of the polymeric orco-polymeric composition described herein as comprising a curcuminoidcompound is such that the concentration of the curcuminoid compound inthe composition does not decrease as a result of extraction step ofUCDs, or decreases by no more than 0.0001%, when subjected to anextraction process in an organic solvent, including also solvents whichcan readily dissolve the curcuminoid compound.

As discussed herein, a curcuminoid compound can be selected according tothe desired light-absorption properties which are required from thecomposition.

According to some embodiments of the present invention, the curcuminoidcan be selected such that the composition is substantially transparentto light at a wavelength ranging from about 400 to about 800 nm, and itcan also be selected such that the composition is substantially opaqueto light at a wavelength ranging from about 190 to about 440, orsubstantially opaque to light at a wavelength ranging from about 100 toabout 400.

Such optical properties were demonstrated for compositions comprisingcurcumin, bisdemethoxycurcumin or monodemethoxycurcumin, as thecurcuminoid compound.

According to some embodiments of the present invention, the curcuminoidcan be selected such that the composition is substantially transparentto light at a wavelength ranging from about 490 to about 800 nm, and itcan also be selected such that the composition is substantially opaqueto light at a wavelength ranging from about 190 to about 440, or fromabout 100 to about 490. Such a composition is effective in reducing oressentially blocking the transmission of violet/blue light.

Such optical properties can be afforded when the curcuminoid compoundis, for example, tetrahydroxycurcumin (THC).

As discussed herein, UV-light is characterized by a wavelength rangingfrom 100-440 nm (some sources state that visible region starts fromabout 390 nm), violet is the color of the short-wavelength end of thehuman visible spectrum ranging approximately 380-450 nm, and blue lightranges 450-475 nm.

According to some embodiments of the present invention, a polymeric orco-polymeric composition as presented herein, which further comprises atleast one curcuminoid compound as described herein is characterized byhaving UV-light blocking properties, wherein the UV-light ischaracterized by a wavelength ranging from 100 nm to 440 nm.

Some curcuminoid compounds exhibit yellow color which leads toabsorption of visible blue and violet light. According to someembodiments of the present invention, the curcuminoid compound is suchthat it acts as a UV absorber as well as blue light blocker.

According to some embodiments, two different additives for radiationprotection can be present in any of the polymeric or co-polymericcompositions described herein, one for UV-stabilization and another forvisible blue light protection.

According to some embodiments of the present invention, any of thecompositions described herein as containing a curcuminoid compound canfurther comprise an additional radiation resistant agent, as describedhereinabove.

Combining the beneficial features imparted by the curcuminoid compoundas described herein with the beneficial features of the hydrophobicco-polymeric compositions described herein result in a vacuole free,glistening free, internal reflection free and tack free co-polymericcomposition, which is protected from the damaging effects of UV lightand meet the requirement of tensile strength, deformation recoveryability and mechanical, optical, biological and toxicologicalrequirements.

Processes of Preparing the Polymeric or Co-Polymeric Compositions:

Any polymeric or co-polymeric composition, according to some embodimentsof the present invention, can be prepared by conventional polymerizationtechniques; however, some processes may be more suitable for ophthalmicor ocular devices.

In general, the compositions are prepared by polymerizing apre-polymerization mixture as described herein. The pre-polymerizationmixture comprises a mixture of monomers, as described herein for thevarious embodiments of the present invention.

For example, for preparing a co-polymeric composition as describedherein, a mixture containing the five types of monomers is used. Forpreparing a polymeric or co-polymeric composition having a curcuminoidcompound incorporated therein or thereon, a mixture containing acrylatemonomers as described herein is used.

Incorporation of the curcuminoid compound can be made while adding thecurcuminoid compound to the pre-polymerization mixture or by contactingthe polymerized (or co-polymerized) composition with the curcuminoidcompound and allowing it to be incorporated thereon.

The pre-polymerization mixture can further comprise other optionalconstituents and additives. Typically, the pre-polymerization mixturefurther comprises a polymerization initiator such as a free radicalpolymerization initiator.

According to an aspect of embodiments of the present invention, there isprovided a process of preparing a polymeric or co-polymeric compositionas presented herein, which is effected by:

admixing a pre-polymerization mixture containing the monomers presentedhereinabove, as well as other optional constituents and additives and afree radical polymerization initiator;

optionally degassing the pre-polymerization mixture so as to remove anydissolved gasses which may interfere with optical clarity of thecomposition by forming vacuoles;

heating said pre-polymerization mixture while stirring;

optionally degassing the pre-polymerization mixture again so as removevolatile residues after heating;

optionally admixing an additional amount of the initiator into thepre-polymerization mixture so as to obtain a polymerization reactionmixture;

admixing a curing agent into the reaction mixture;

casting the reaction mixture into a mold;

exposing the reaction mixture in the mold to curing conditions, tothereby obtain the co-polymer composition presented herein; and

subjecting the co-polymeric composition to a multiple extraction so asto rid it from unreacted contaminants.

According to some embodiments of the present invention, thepre-polymerization mixture comprises the first, second, third, fourth,and fifth monomers in their appropriate ratios, as described herein fora hydrophobic co-polymeric composition.

According to some embodiments of the present invention, one of theadditives can be a curcuminoid compound, as discussed hereinabove.

Optionally, heating the pre-polymerization mixture while stirring isperformed at 40° C. until the viscosity of pre-polymerization mixturereaches an optimal level (120 cps at 25° C.). The viscosity measurementsare obtained from the torque applied on the stirring device.

Once all the monomers and other components are mixed together forpolymerization, the polymerization reaction may be initiated by adding aradical polymerization initiator in a conventional manner to obtain thepolymeric or co-polymeric composition according to some embodiments ofthe present invention.

The choice of initiator also determines the kinetics of thepolymerization reaction. As discussed hereinabove, the molecular weightof the composition confers properties to the ophthalmic device madetherefrom, such as glistening, mechanical properties, refractive indexand transmittance. Molecular weight is inversely proportional to thehalf power of the initiator concentration.

The initiator, also referred to herein as a catalyst, is typicallyemployed to initiate the polymerization of the monomers and/or carry outthe crosslinking or thermosetting of the polymeric or co-polymericcompositions formed of those monomers, as presented herein. Thus,according to some embodiments of the present invention, the co-polymericcomposition present herein further includes an initiator (a catalyst).

According to some embodiments of the present invention, thepolymerization reaction follows a free-radical propagation mechanism. Asknown in the art concerning conventional polymerization methods, thefree-radical polymerization reaction may be initiated, for example, byfree radical initiators, either thermally or photochemically. When usinga thermally initiated free radical polymerization reaction, the methodis typically effected by heating gradually from room temperature to anelevated temperature, such as 130° C., and the temperature can beelevated stepwise and/or cycled. When the polymerization initiator iscontrolled photochemically, the polymerization reaction in initiated byirradiating the pre-polymerization mixture with electromagneticradiation, such as microwave, ultraviolet light or radiation (γ ray)after a radical polymerization initiator is added thereto. It is notedherein that two or more types of initiators may be combined to arrive ata more controlled and completed polymerization reaction.

According to some embodiments of the present invention, the initiationstep is effected at relatively low temperatures as a function of thechoice of initiator. According to some embodiments of the presentinvention, the co-polymeric composition includes a low temperaturedissociation initiator which keeps the formed device fixed in positionin the mold by avoiding significant expansion or contraction. Using suchinitiators makes the use of fused silica molds redundant, which in turnreduces the need for complex UV-curing of the composition. Hence,according to some embodiments of the present invention, the initiator isa low temperature dissociation initiator.

According to some embodiments of the present invention, non-limitingexamples of the initiator include bedicetyl peroxydicarbonate,tert-butyl peroxypivalate, diisobutyryl peroxide, dimyristylperoxydicarbonate, 1,1,3,3-tetramethylbutyl peroxypivalate, tert-butylperoxyneoheptanoate, di(2-neodecanoylperoxy-isopropyl)benzene,cumylperoxy-neodecanoate, 1,1,3,3-tetramethylbutylperoxy-neodecanoate,t-butylperoxy-neodecanoate, t-butylperoxy-neoheptanoate and anycombinations thereof.

According to other embodiments of the present invention, the catalyst isselected from the group consisting of dicetyl peroxydicarbonate (such asPerkadox® 24L by Akzo Nobel Polymer Chemicals, India) and tert-butylperoxypivalate (such as LUPEROX® 554M75 by Arkema Inc. Philadelphia,Pa., USA).

Non-limiting examples of a radical and/or thermal polymerizationinitiator include, for instance, azobisisobutyronitorile,azobisdimethylvaleronitrile, benzoyl peroxide, tert-butyl hydroperoxide,qumene hydroperoxide and the like, which can be used solely or in acombination use of two or more thereof.

Light-sensitive initiators (photopolymerization initiator) include, fora non-limiting example, photopolymerization initiators of benzoincompounds such as methyl orthobenzoyl benzoate, methyl benzoyl formate,benzoin methyl ether, benzoin ethyl ether, benzoin isopropyl ether,benzoin isobutyl ether and benzoin n-butyl ether, photopolymerizationinitiators of phenone compounds such as2-hydroxy-2-methyl-1-phenylpropane-1-one,p-isopropyl-α-hydroxyisobutylphenone, p-tert-butyltrichloroacetophenone,2,2-dimethoxy-2-phenylacetophenone, α,α-dichloro-4-phenoxyacetophenone,and N,N-tetraethyl-4,4-diaminobenzophenone,1-hydroxycyclohexylphenylketone,1-phenyl-1,2-propanedione-2-(o-ethoxycarbonyl) oxime,photopolymerization initiators of thioxanthone such as2-chlorothioxanthone and 2-methylthioxanthone, dibenzosuberone,2-ethylanthraquinone, benzophenone acrylate, benzophenone, benzil andthe like.

The amount of the above-mentioned polymerization initiator is typicallynot less than 0.002 percent by weight, more preferably 0.01% by weightbased on 100% of the total weight of the composition. Alternatively, theconcentration of the initiator is not more than 10% by weight, or notmore than 2% of the total weight of the composition.

The optional addition of initiator (also referred to hereininterchangeably as a catalyst) prior to the casting stage, is meant toboost the completion of the polymerization reaction. As discussedhereinabove, additional initiator is added when the viscosity of thereaction mixture reaches about 120 cps.

According to some embodiments of the present invention, the processincludes first adding an amount equivalent to about 20-40% of the totalamount of the initiator in the first step of the process, and thenadding about 60-80% of the total weight of the initiator.

After mixing and adding the initiator, the mixture is transferredthrough a filter into the mold. The viscosity at which the mixture isfiltered is about 120-130 cps. The ophthalmic device is formed in themold from the mixture directly into its complete form, avoiding furthermachining which in turn avoids local burning and machining relatedstresses. After casting or pouring the mixture in between two halves ofthe mold, thermal or photo curing stimulus is applied. Thermal curing isperformed at room temperature to 80° C. with several ramping steps.

According to some embodiments of the present invention, filtering thereaction mixture may also precede the casting stage.

Once the reaction mixture is cast in a mold, the curing step can start.Exposure to curing conditions typically includes elevating thetemperature and/or exposing the reaction mixture to high energyradiation. High temperatures are typically about 80° C., and theirradiation energy may range from 10 KJ/Kg to 50 KJ/Kg in order tofurther allow the co-polymeric composition to cure.

Curing agents and accelerators may also be employed in the formation ofthe co-polymeric composition according to some embodiments of thepresent invention. Various curing agents and accelerators are known andcan be used in prescribed amounts or amounts experimentally found to besuitable. Typically, amounts of the curing agent, the curing agentaccelerator or a combination thereof are between about 0.1% and about 8%by weight of the total weight of the composition. Curing agents andaccelerators can be used in various amounts, which will typically dependupon the monomers and polymers being employed, any ambient conditions(e.g., heat, light or otherwise) being used for curing and/or otherfactors.

Examples of suitable curing agents include UV photoinitiators, peroxycatalysts (i.e., any catalyst including a peroxy group), oxide catalysts(i.e., any catalyst include an oxide group (e.g., a dioxide) or othersknown by the skilled artisan. One example of a peroxy catalyst is atert-butyl peroxy-2-ethylhexanoate organic peroxide initiator, which isparticularly suitable for thermal cure. One example of an oxide catalystis 2,4,6-trimethylbenzoyldiphenylphosphine oxide, which is particularlysuitable for blue light cure.

According to some embodiments of the present invention, the monomers,the initiator, the curing agent and optionally curing agent accelerator,a UV-blocker (radiation resistant compound), if present, and any otherdesired ingredients are combined together to form a master batch. Themaster batch is then exposed to an ambient stimulus, such as heat orlight (e.g., blue light) which initiates polymerization andcross-linking reactions between the various monomers. The initiatedmaster batch can be cast into molds (such as cast wafers) of desiredgeometry and can be secured in cure fixtures for forming the ophthalmicdevices. It is advisable to add a crosslinking monomer in initial stageespecially in the case where the polymerization reaction is performed atrelatively low temperature.

The wafer molds are then typically cured through extended exposure to anambient condition such as heat, light or both. For example, in oneembodiment, the cast wafers are exposed to an elevated temperature(e.g., about 70° C.) for a first period of time (e.g., about 2 hours)and then ramped up to a second temperature (e.g., about 110° C.) for asecond period of time (e.g., at least 10 minutes). In a second exemplaryembodiment, the wafers are cured using blue light at a wavelength ofabout 405 nm to about 415 nm for a first period of time (e.g., about 3hours) and then exposed to an elevated temperature (e.g., about 110° C.)for a second period of time (e.g., about one hour). Typically, theinitiation, the curing or both are carried out in a low moisture (e.g.,less than 1 ppm water) and low oxygen (less than 100 ppm) environment.

Alternatively, working at relatively low temperatures, from roomtemperature and up to 80° C. is advantageous, since it allows thepolymerization and curing steps to complete post the casting stage(namely in the mold), without causing thermal distortion of the mold.This way a relatively low cost polypropylene mold can be used, insteadof a costlier fused silica molds.

During the initial polymerization step it is possible to monitor theviscosity of the master batch mixture, for example by following theforce applied to the mixing shaft.

Once the polymeric or co-polymeric composition is cured it can becleansed from unreacted components and other leachables. The extractionof leachables may commence once the molded and cured composition isreleased from the mold. According to some embodiments of the presentinvention, the extraction is effected by sequential immersion of thepolymeric or co-polymeric composition in a series of baths, eachcontaining a different solvent or solution, going from hydrophobic tohydrophilic in the order of sequence, thereby extracting unreactedcontaminants from the composition.

Following the description of the embodiments of the present invention,provides polymeric and co-polymeric compositions and processes forpreparing the same, which are highly suitable for manufacturingimplantable and non-implantable ophthalmic and ocular devices. Followingthe above-described description of the embodiments affords vacuole free,glistening free, internal reflection free and tack free ophthalmic andocular devices, which meet the requirement of tensile strength,deformation recovery ability and mechanical, optical, biological andtoxicological requirements set by widely accepted standards of the art.

It is noted that even after the post-curing step, which further pushesthe polymerization reaction to completion, some impurities fromunreacted monomers and other contaminants remains in the composition.These impurities are commonly referred to herein as unreactedcomponents, diluents and other leachable impurities. Under the termleachable impurities are also included filter membrane residues, boilingimpurities, solvent remnants and other process contaminants.

To remove unreacted components and diluents (UCDs) and other leachableimpurities from the cured composition, and affect clinical viability ofthe device, the process of preparing such devices typically includes anextraction step. If the leachable substances are not extracted from thedevice, they may make the device uncomfortable to wear or even present amedical hazard. As used herein, “leachable substance” includes UCDs andother substances which are not bound to or embedded in the polymer andmay be extracted from the composition (the matrix), for example, byleaching with water or an organic solvent. As used herein, the term“treat” means to expose a cured object or device, made from thecomposition presented herein, to an aqueous and/or organic solutionwhich may also include at least one leaching aid. Treating a curedpolymeric composition to remove UCDs and monitoring traces thereof isdemonstrated in the Examples section which follows below using acurcuminoid compound as a light-stabilizer, which is not part of thepolymeric backbone and therefore required not to leach out of the curedcomposition.

As used herein, a “leaching aid” is any compound that if used in aneffective amount in an aqueous or organic solution to treat anophthalmic device, and can assist in obtaining a device with an adequateamount of removal of leachable substances.

According to embodiments of the present invention, the process ofpreparing the co-polymeric composition presented herein may include atreatment of the cured co-polymeric composition. The treatment step caninclude exposing the cured composition to an aqueous and/or organicsolution which constitutes or includes at least one leaching aid. Invarious embodiments, treatment can be accomplished, for example, viaimmersion of the device in a solution or exposing the device to a flowof solution or exposing the device to Soxhlet extraction. In variousembodiments, treatment can also include, for example, one or more ofheating the solution; stirring the solution; mechanical agitation orsonication of the solution; and increasing the level of leach aid in thesolution to a level sufficient to facilitate adequate removal ofleachable substances from the device.

According to some embodiments of the present invention, an organic oraqueous solution may constitute a leaching aid. According to otherembodiments of the present invention, leaching aids can also be combinedwith organic solvents to improve the rate of release. For example, insome embodiments, ophthalmic devices such as lenses can be subjected toa treatment exposing the lens devices to a leaching aid and a GC MassSpectrometer can be used to measure the level of one or more leachablesubstances in the lens devices. The GC Mass Spectrometer can determinewhether treatment with a particular leaching aid is effective to reducean amount of particular leachable substances present in the lenses to amaximum threshold amount. Accordingly, in some embodiments, a GC MassSpectrometer can be used to check for a maximum threshold of leachablesubstances of approximately 300 ppm. A minimum hydration treatment timeperiod necessary to reduce the presence of such leachable substances to300 ppm or less in specific lenses can be determined by the periodicmeasurements. In additional embodiments, other leachable substances,such as, for example, D30 or other diluents, can be measured to detectthe presence of a maximum amount of approximately 60 ppm. Embodimentscan also include setting a threshold amount of a particular leachablesubstance at the minimum detection level ascertainable by the testingequipment.

Examples of leaching aids, according to the present invention include,without limitations, alkanes, ketones (e.g. 2-butanone), amides, ethers(e.g. THF), alcohols (e.g. methanol), esters (e.g. ethyl acetate),aldehydes, nitrogen-containing cyclic compounds, toluene, water,ethoxylated alcohols or ethoxylated carboxylic acids, ethoxylatedglucosides or sugars, optionally with attached C₆-C₁₄ carbon chains,polyalkylene oxides, sulfates, carboxylates or amine oxides of C₆-C₁₄compounds. Examples include cocamidopropylamine oxide, C₆-C₁₄ fattyalcohol ethoxylated with ethylene oxides, sodium dodecyl sulfate,polyoxyethylene-2-ethyl hexyl ether, polypropylene glycol, polyethyleneglycol monomethyl ether, ethoxylated methyl glucoside dioleate, and thesodium salt of n-octylsulfate, sodium salt of ethylhexyl sulfate.

By way of non-limiting examples, various implementations can includerelease and removal of leachable impurities that is accomplished by wayof a batch process wherein devices are submerged in a solution containedin a fixed tank for a specified period of time or in a vertical processwhere devices are exposed to a continuous flow of a solution thatincludes at least one of a leach aid. In some embodiments, the solutioncan be heated with a heat exchanger or other heating apparatus tofurther facilitate leaching of the device. For example, heating caninclude raising the temperature of an aqueous or organic solution to theboiling point while a device is submerged in the heated solution. Otherembodiments can include controlled cycling of the temperature of thesolution. Some embodiments can also include the application of physicalagitation to facilitate leach. For example, a strainer container holdingthe device can be vibrated or caused to move back and forth within aleaching solution. Other embodiments may include ultrasonic wavesthrough the solution.

The choice of a leaching aid or solvent depends on the impuritiespresent in the composition. Each solvent has a capability of extractingcertain impurities with an overlapping range of chemical efficiency. Forexample, 2-butanone, THF, methanol and ethyl acetate are usedsequentially on a same set of fully cured devices; which helps inremoving all identified impurities step by step. Water miscible solventsare kept for last. A continuous soxhlet extraction may be employed whichutilizes fresh solvent each time. Each soxhlet extracting phase may besized to hold 500 lenses of 20 diopter. Maximum quantity varies with thepower for given sized extractor. However extractors can be easily scaledup to meet the quantity requirement. Flow rate for the solvent variesaccording to extractor and according to cycle time. A holding time of 3hours is kept for each solvent. For example, a drop rate of 100 ml/hr iskept for 300 ml extractor.

For example, freshly cured ophthalmic or ocular devices, prepared fromthe polymeric or co-polymeric composition presented herein, are kept inglass thimble, which is soaked in a bath of one leaching aid solution,and then exchanges its position to a bath holding the next solvent andso on; wherein each soak is maintained for 15-30 minutes. A vacuumtempering is performed thereafter in order to dry the devices at 110° C.and 0.1 mbar.

According to some embodiments of the present invention, post operationof reducing tack may be performed on a anterior surface or on bothsurface by processing lens by methods such as plasma treatment, surfacefluorination, bulk fluorination, hydrophilic coating, irradiating withEB rays, high energy UV rays or by other energy intensive rays, use ofinternal wetting agents for selective migration and allied.

Ophthalmic Device Made from Polymeric or Co-Polymeric Compositions:

The polymeric or co-polymeric composition as described herein,optionally having a curcuminoid compound incorporated therein or thereonas described hereinabove, can be used to form any ophthalmic or oculardevice.

Any ophthalmic or ocular device, typically a lens, formed from any ofthe compositions presented herein, can be manufactured by using one ortwo basic methods: molding into a final form without further machining,and shaping and molding followed by machining for reshaping andpolishing. Hence, a device as described hereinbelow, made from apolymeric or co-polymeric composition as presented hereinabove, can bemade while preparing the polymeric or co-polymeric composition, orprepared from a pre-formed polymeric or co-polymeric composition.

For example, multi-part molds can be used to fashion the compositionpresented herein into a useful article of a complex shape, such as anophthalmic device or any other type of lens. In the case of a lens, themulti-part molds can include for example, a first mold part with aconvex or concave surface that corresponds to a back curve of anophthalmic lens, and a second mold portion with a generally convexsurface that corresponds to a front curve of the lens. To prepare a lensusing such mold portions, the uncured lens' composition is placedbetween the mold portions and subsequently cured. The lens' compositionmay then be cured, for example by exposure to either or both heat andlight. The cured composition forms a lens body according to thedimensions and features of the mold portions. Following curing,traditional practice dictates that the mold portions are separated andthe lens remains adhered to one of the mold portions, calling for arelease process to detach the lens from the remaining mold part. In someembodiments, the process of manufacturing the lens body, the cured lensbody may be subjected to further polishing and/or shaping to achievefinal desired form.

The formation of the ophthalmic device from the composition presentedherein can also be effected by, for example, a computer-controllablemanufacturing device. For example, the ophthalmic or ocular devicepresented herein may be shaped into final form in two basic steps,wherein in the first step the crude lens is forged from the co-polymericcomposition presented herein, and in the second step other structuralfeatures are formed in the cured crude lens body using a computercontrollable manufacturing device.

A “computer controllable manufacturing device” refers to a device thatcan be controlled by a computer system and that is capable of producingdirectly a lens body or a mold for producing an ophthalmic device. Anyknown, suitable computer controllable manufacturing device can be usedin the invention. Exemplary computer controllable manufacturing devicesinclude, but are not limited to, lathes, grinding and milling machines,molding equipment, and lasers. In various exemplary embodiments of theinvention a Computerized Numeric Controlled (CNC) lathe machine can beused, such as the lathers marketed under the trade names DAC™ Vision,Optoform and CareTec.

Some ophthalmic and ocular devices, formed from any of the compositionspresented herein, may require different techniques and protocols knownin the art.

According to an aspect of some embodiments of the present inventionthere is provided an ophthalmic device comprising any of the polymericor co-polymeric composition presented herein.

It is noted herein that the polymeric or co-polymeric compositionspresented herein containing a curcuminoid compound may constitute anyophthalmic or ocular device, such as a lens, that is prepared therefrom.The polymeric and/or co-polymeric compositions described herein conferthe refractive index, strength, transparency, vacuoles, halos,UV-stabilization and other traits, characteristics and parameters, tothe products made therefrom.

In some embodiments of this aspect, a composition as described herein isformulated for insertion into or onto an eye, namely it is required tobe bio-compatible, chemo-compatible and physico-compatible in order tobe used in an ophthalmic device.

The present embodiments also contemplate a method of treating vision ofa subject in need thereof using any ophthalmic or ocular device madefrom any of the compositions described herein. The method is effected byinserting, applying and/or implanting the ophthalmic or ocular device inan eye of the subject, thereby treating the vision of the subject. Themethod can be exercised, for example, while or subsequently to acataract surgery. The devices disclosed herein can be beneficially usedto correct standard optical distortions and in the treatment ofophthalmic conditions, such as for example, retinal detachment;occlusions; proliferative retinopathy; proliferative vitreoretinopathy;diabetic retinopathy; inflammations such as uveitis, choroiditis, andretinitis; degenerative disease (such as age-related maculardegeneration, also referred to as AMD); vascular diseases; and varioustumors including neoplasms.

The devices may take the form of a multifocal ophthalmic device, amonofocal ophthalmic device, a contact lens, an implantable ophthalmicdevice, an intraocular lens (IOL), a keratoprosthesis, a phakic lens, anaphakic lens, a corneal ring, a capsular bag extension ring, a cornealinlay and a corneal onlay may be used in the treatment of an opticaldistortion, a retinal detachment, an occlusion, proliferativeretinopathy; proliferative vitreoretinopathy, diabetic retinopathy, adegenerative disease and an age-related macular degeneration.

It should be noted herein that according to some embodiments of thepresent invention, any of the compositions presented herein can be usedto manufacture ophthalmic devices used also for drug delivery. In theseembodiments, the non-leachability of the main additives and components(such as, for example, the curcuminoid compound discussed hereinabove)is in effect, however, the drug which is delivered from the device tothe surrounding tissue is in fact leachable, and can diffuse from thematrix (typically a hydrogel) to the physiological medium in which thedevice is situated and from there to the tissue to be treated.

Additional features of the ophthalmic device, co-polymeric compositionand/or polymeric or co-polymeric composition incorporating a curcuminoidtherein are described in International Patent Application No.IB2010/053818 and in Indian Patent Application Nos. 1938/MUM/2010 and2888/Mum/2010, the teachings of which are incorporated by reference asif fully set forth herein.

It is expected that during the life of a patent maturing from thisapplication many relevant polymeric and co-polymeric compositions, withand without curcuminoid compounds, for ophthalmic and ocular deviceswill be developed and the scope of such compositions is intended toinclude all such new technologies a priori.

As used herein the term “about” refers to ±10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

The word “exemplary” is used herein to mean “serving as an example,instance or illustration”. Any embodiment described as “exemplary” isnot necessarily to be construed as preferred or advantageous over otherembodiments and/or to exclude the incorporation of features from otherembodiments.

The word “optionally” is used herein to mean “is provided in someembodiments and not provided in other embodiments”. Any particularembodiment of the invention may include a plurality of “optional”features unless such features conflict.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “treating” in the context of a medicalcondition, includes abrogating, substantially inhibiting, slowing orreversing the progression of a condition, substantially amelioratingclinical or aesthetical symptoms of a condition or substantiallypreventing the appearance of clinical or aesthetical symptoms of acondition.

As used herein, the term “treating” in the context of an objectundergoing an industrial and/or mechanical and/or technical process,includes improving, refining, or otherwise advancing the progression ofthe process with respect to the object.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below find experimentalsupport in the following example.

EXAMPLES

Reference is now made to the following example, which together with theabove descriptions illustrates some embodiments of the invention in anon limiting fashion.

Example 1 Co-Polymeric Composition—Materials and Methods

2-phenoxyethyl acrylate (POEA) was obtained from Sigma-Aldrich, India,and used as an exemplary aromatic monomer characterized as forming ahomopolymer having a refractive index of that ranges from 1.50 to 1.53(first aromatic acrylate monomer).

2-phenylethyl acrylate (PEA) was obtained from Polysciences Inc., andused as an exemplary aromatic monomer characterized as forming ahomopolymer having a Tg lower by 2-30° C. than a Tg of the homopolymerof POEA (second aromatic acrylate monomer).

2-methoxyethyl methacrylate (MOEMA) was obtained from Sigma-Aldrich,India, and used as an exemplary monomer characterized as forming ahomopolymer having a Tg lower than 35° C. (third monomer).

The above monomers were used after high vacuum distillation for removalof polymerization inhibitors and impurities such as correspondingalcohols and acid.

2-hydroxyethyl methacrylate (HEMA) was obtained from Sigma Aldrich,India, and used as is, as an exemplary monomer characterized as forminga homopolymer which is capable of absorbing water to at least 20% of itstotal weight (fourth monomer).

1,4-butane diol diacrylate (BDDA) was obtained from Sartomer, Asia, andused as is, as an exemplary crosslinking monomer. The incorporation of acrosslinking monomer depends on the intended/desired unfolding time,flexibility, loop pull force and compression force. This exemplarycrosslinking monomer is being selected as suitable in the development ofan IOL which requires a short unfolding time of less than or equal to 5seconds (fifth monomer).

2,2′-azobis-(2,4-dimethylvaleronitrile) (AIVN) was obtained from HPLPolymer Additives, India, and used as is, as an exemplary initiator.

2-(5-chloro-2H-benzotriazole-2-yl)-6-(1,1-dimethylethyl)-4-methyl-phenol(TINUVIN® 326) was obtained from Ciba Specialty Chemicals, India, andused as is, as an exemplary UV absorber of thehydroxyphenylbenzotriazole class.

4-[(E)-phenyldiazenyl]-phenyl-2-methacrylate was synthesized in theinventor's laboratory, and used as an exemplary yellow dye.

Refractive Index:

The refractive index of some exemplary polymeric compositions presentedhereinbelow was determined following the ASTM D542-2000 standard usingan Abbe refractometer prisms system (ATAGO U.S.A., Inc, Model DR-A1).

Tested specimens are cut to blocks of 1 mm thickness, 10 mm width and 50mm length. The blocks are fitted on the face of the fixed half of therefractometer prisms system. Both surfaces are polished to the extentthat sharply defined straight dividing line is seen. Three specimens areprepared for each batch of polymeric composition. Conditioning is doneat 23±2° C. and 50±5% relative humidity for no less than 40 hours priorto test, and the test is conducted at same conditions.

Mechanical Strength:

The mechanical strength (also referred to herein interchangeably as the“loop pull force”) of some exemplary polymeric compositions presentedhereinbelow was determined following the ISO 11979-3:2006 standard usinga standard tensometer (Universal Testing Machine, Lloyd's LF plus with10N load cell).

Lenses prepared from polymeric compositions according to someembodiments of the present invention, were conditioned at 23±2° C. and50±5% relative humidity for not less than 40 hours prior to testing, andthe tests were conducted at same conditions.

The lenses were clamped so that the direction of the pull was tangentialto the loop at the loop/optic junction in the tensometer. The extensionrate was set at 1 mm/minute and the tensometer was activated. The lenswas pulled until the loop broke or separates from the lens and theYoung's modulus value recorded.

Glass Transition Temperature (Tg):

The glass transition temperature of some exemplary polymericcompositions presented hereinbelow was determined following the ASTMD3418-03:2000 standard using a differential Scanning colorimeter(Shimadzu Scientific Instruments, Model DSC 60A).

Polymeric composition specimens' mass was 15 mg. Helium was purgedduring weighing and testing, and the weighing was performed at anaccuracy of ±10 μg.

A preliminary thermal cycle was performed and recorded by cooling thesample at a rate of 20° C. per minute from at least 37° C. to −50° C.The temperature was maintained for five minutes at 37° C. and thereafterquenched to −50° C. and maintained at that for five minutes. Thiscooling cycle was repeated at a rate of 20° C. per minute and thecooling curve was recorded until distinct lineaments of glass transitiontemperature have been completed.

Shore A Hardness:

The Shore A hardness of some exemplary polymeric compositions presentedhereinbelow was determined following the ASTM D2240:2000 standard usinga digital Shore A hardness meter (Mitutoyo America Corporation, ModelHH-336-01).

Digital Shore A hardness meter was attached to a constant pressurehardness measurement stand. A sample of a polymeric composition,according to some embodiments of the present invention, was placedexactly within the shaped cavity, and a side lever was pressed until thereading of the pressure gauge was constant, and the Shore A hardnessvalue was recorded.

Visible Light Transmission:

The visible light transmission of some exemplary polymeric compositionspresented hereinbelow was determined following the ASTM D 1003 standardand using a visible light spectrophotometer (Varian, Inc., Model Cary50).

Samples of the polymeric composition according to some embodiments ofthe present invention, were cut to blocks of 1 mm thickness, 10 mm widthand 50 mm in length so as to fit into the polished face of a quartzcuvette. Both surfaces of the sample were polished to the extent that nogap is seen between the cuvette surface and sample. Such highly polishedsurface, typically to an IOL, is needed to minimize the losses due toair interface scattering. Three samples were prepared from eachpreparation batch, and conditioned at 23±2° C. and 50±5% relativehumidity for at least 40 hours prior to testing, and testing wasconducted at same conditions.

The spectrum of the test was set from 250 nm to 800 nm in UV-Visspectrophotometer panel, and the sample was scanned through the wholespectrum of wavelengths while recording the transmission results.

Unfolding Time:

The unfolding time of the finished lens product, prepared from polymericcompositions according to some embodiments of the present invention, wasdetermined using an injector, a cartridge and a stopwatch.

A 1.85 mm diameter sterile cartridge was filled with Visco elastic(Viscolon) solution or another suitable delivery medium, and the testedlens was placed in by means of forceps. The lens was put into thecartridge folded while letting the interior surfaces come in contact.The cartridge was loaded into the injector, and excess Viscolon wasforced out of the cartridge. The injector plunger was pressed smoothlyso as to force the lens comes out of the cartridge onto a Petri dishwhich filled with 0.9% saline at 25° C.

The exact time interval for unfolding was recorded with a precise stopwatch, started from the point when the lens comes out of cartridge andup to the point when it is completely relaxed in the saline and unfoldsfully, and this time interval was defined as the unfolding time for aparticular lens sample.

Glistening Test:

The glistening of the finished lens product, prepared from polymericcompositions according to some embodiments of the present invention, wasdetermined using a microscope.

The lens was immersed in physiological medium such as 0.9% salinesolution, and kept at 40° C. in forced air circulatory oven for 72hours. The lens was thereafter cooled while immersed in the saline for aperiod of 3 hours, and thereafter observed under a 50× microscope forexamination for vacuoles and glistening.

Extractables and Leachables Content:

The extractables and leachables content (also referred to herein as theleachable content) in samples of the polymeric composition according tosome embodiments of the present invention, was determined following theISO 11979-5:2006 and ISO 11979-5:2006 standards and using standardgravimetric analysis.

A number of exemplary lenses were dried under vacuum at 60° C.±5° C. forthree hours, and thereafter allowed to cool to room temperature undervacuum before weighing. The lenses were weighed to the nearest 0.1 mgand placed in an extraction thimble. Boiling stones were placed in theflask, and the flask was filled to about 50% of its capacity (about 250ml) with THF.

The extraction thimble was placed in a Soxhlet apparatus fitted with theflask and a condenser. The flask was heated with a mantle and whilechilled water was circulated through the condenser. The extraction ratewas set at about 4 thimble flushes per hour and the lenses were extractfor 3 hours.

At the end of the extraction cycle the solvent was allowed to cool toroom temperature and the thimble with the lenses was removed fromextractor. The lenses were put in a Petri dish under laminar flow, andcarefully separated from each using PTFE coated forceps. The extractedlenses were dried to constant mass in a vacuum oven.

The total weight of the dried lenses was determined after the firstextraction cycle and the change in weight effected by the extraction wasrecorded.

The procedure was repeated with methyl ethyl ketone and methanolrespectively with new thimbles.

Dioptric Power:

The resulting dioptric power was compared to the expected dioptric powerfollowing the ISO 11979-2:1999 standard and using a standard dioptricpower measuring device (ROTLEX Ltd., Israel, Model IOLA Plus).

The expected dioptric power was determined using dimensionally detailspertaining to the casting halves of the mold. Such a test can identifyuneven or greater shrinkage in the cast which may lead to unacceptableoptic parameters or variation in the dioptric power, leading todisqualification of a lens product. A process of extraction mainlycontributes to the uneven shrinkage.

The pre-polymerization mixture of the polymeric composition according tosome embodiments of the present invention, was cast in mold halves andprocessed subsequently to form an IOL.

The power of the lens was measured at the end of process and recordedtogether with the difference in the expected dioptric power.

Tackiness:

The tackiness of the finished lens product was determined following ASTMD 3654 standard and using a standard tensometer (Universal TestingMachine, Lloyd's LF plus with 10N load cell).

A tested polymeric composition was formed and cast as a lens but in aform of strips having dimension 50 mm in length, 10 mm in width and 1 mmin thickness.

Posterior surface of two strips were faced towards each other andpressed by 200 gm weight for 24 hour at 25° C., thereby forming a singlelap shear joint. 10 mm edges were left unattached at either end of thestrips intentionally. These ends were used for gripping in a fixtureattached to universal testing machine (mechanical testing machine).

Thereafter the joint strips were vertically aligned and stretched atconstant rate of elongation of 2 mm per minute.

A peak force reading point of break was recorded. This was determined asthe shear force required to separate the joint strips which, and assignas the measure of tackiness or self adhesion integrity.

Modular Transfer Function:

The modular transfer function (MTF) of some exemplary polymericcompositions presented hereinbelow was determined following the ISO11979-2:1999 standard and using a standard model eye (ROTLEX Ltd.,Israel, Model IOLA Plus).

Samples of IOL, prepared from the polymeric composition according tosome embodiments of the present invention, was placed in cuvette filledwith saline and a converging beam from the model cornea exposed thecentral circular 3.00 mm±0.1 mm of the lens. The difference inrefractive index between the lens and the liquid medium was recordedwithin 0.005 units of that under in situ conditions.

The lens front surface was placed at a plane between 27 mm to 28 mm infront of the focal point of the model cornea itself, taking refractiveindex of the image space to be 1.336. The light source was by filtrationor otherwise confined to 546 nm±10 nm.

The procedure was performed while ensuring that the lens is in thecorrect position, and that the whole unit is well aligned with theoptical axis of the bench, and focused to obtain maximum MTF at 100lines per millimeter while recording the MTF value.

Example 2 Polymerization Mixture and Reaction

Following are formulations and a process for forming an exemplarypolymeric composition, according to some embodiments of the presentinvention.

General Procedure:

Prior to weighing, all monomers are degassed for 30 minutes in adegasser operating at 50 mm Hg vacuum.

All monomers, initiator, UV absorber and yellow dye are mixed in areaction kettle at room temperature until the liquid mixture becomeshomogenous and clear.

After blending, nitrogen is purged for 15 minutes by bubbling though themixture, and the mixture is added to a stirred autoclave reactor andheated to 40° C. while stirring with a three-blade propeller under a 2Kg nitrogen pressure.

When the amount of unreacted volatile matter drop below 30% w/w and theviscosity reach 120±10 cps at 25° C., the reaction mixture is cooled to−30° C. in an oil bath, and thereafter is allowed to warm up to roomtemperature.

Thereafter additional initiator is added to the reaction mixture whilemixing the mixture until all the initiator is fully dissolved.

Preparation of an Exemplary Composition:

Exemplary co-polymeric composition, denoted Ex. 0 hereinafter, wasprepared as follows.

Prior to weighing, all monomers were degassed for 30 minutes in adegasser operating at 50 mm Hg vacuum. The exemplary formulationpresented below represents a batch size of 600 grams.

342 grams of 2-phenoxyethyl acrylate, 102 gm of 2-phenyl ethyl acrylate,90 grams of 2-methoxyethyl methacrylate, 54 grams of 2-hydropxy ethylmethacrylate, 12 grams of 1,4-butane diol diacrylate, 0.3 grams of2,2′-azobis(2,4-dimethylvaleronitrile), 1.2 grams of TINUVIN® 326(benzotriazole UV absorber) and 0.72 grams of4-[(E)-phenyldiazenyl]-phenyl-2-methacrylate (yellow dye) were added toa 1 liter reaction kettle, and mixed at room temperature until theliquid mixture became homogenous and clear.

After blending, nitrogen was purged for 15 minutes by bubbling thoughthe mixture, and the mixture was added through an addition funnel to astirred autoclave reactor and was heated to 40° C. while stirring with athree-blade propeller under a 2 Kg nitrogen pressure. The solutionbecame gradually viscous while monomer entities turn to high molecularweight chains.

When the amount of volatile matter, mainly unreacted monomer entitiesand short oligomers, had dropped below 30% w/w, as required by the ASTMD 1353-09 standard, and the viscosity has reached 120±10 cps at 25° C.,as determined by measuring torque experienced by stirrer shaft connectedto constant RPM motor, the reaction mixture was cooled to −30° C. in anoil bath, and thereafter allowed to warm up to room temperature.

Thereafter 1.2 grams of the initiator2,2′-azobis(2,4-dimethylvaleronitrile) were added to the reactionmixture while mixing the mixture until all the initiator was dissolvedtherein.

The above exemplary polymeric composition, referred to herein as “Ex.0”, was prepared from the exemplary formulation presented above, havingthe following proportions:

POEA—56%;

PEA—17%;

MOEMA—15%;

HEMA—9%;

BDDA—2%;

AIVN—0.05% initial aliquot plus 0.2% second aliquot;

UV absorber—0.2%; and

Yellow Dye—0.12%.

The final homogenous mixture of Ex. 0 was filtered through 0.2 micronPTFE membrane disc filter and placed into a dosing pump.

Example 3 Intraocular Lens Product Molding and Post-Molding Workup

The polymerization mixture was prepared as described hereinabove, acuring agent was added thereto and the mixture was dispensed intointraocular lens polypropylene mold halves.

The mixture was cured in a temperature cycle of 40° C. for 12 hours; 45°C. for 6 hours; and 50° C. for 6 hours.

As discussed hereinabove, intraocular lenses, prepared as describedhereinabove, may contain impurities such as un-reacted monomers,crosslinker, initiator and other residues, which may leach out into thephysiological aqueous media once implanted in the eye. In order tocleanse the product, a multi-solvent extraction procedure was used toremove these impurities as described below.

About 30 intraocular lenses were placed in an immersible lens mountfitted to a 60 ml extractor vessel (obtained from Sigma Aldrich, India).The extractor vessel was filled with an alcohol such as isopropanol, andthe lenses were kept therein under reflux temperature for 9 hours. Thisprocedure was repeated using a ketone such as acetone. Thereafter thelenses were dried in a vacuum oven at 10 mm of Hg and 110° C.

After drying, the cleansed lenses were treated with EB rays (electronbeam) to quench unreacted monomers and reduce tack on the interior andexterior surfaces.

Example 4 Additional Formulations

Lens products made from other exemplary formulations for polymericcompositions, according to some embodiments of the present invention,were prepared by following the aforementioned procedures for preparationof the pre-polymerization mixture, polymerization reaction, molding andpost-molding workup.

Table 1 presents additional exemplary formulations for polymericcompositions according to some embodiments of the present invention,wherein the resulting compositions are denoted Ex. 1-10, and eachcomponent is presented in its relative content in weight percentage ofthe total weight of the composition.

TABLE 1 UV Yellow Component POEA PEA MOEMA HEMA BDDA AIVN absorber DyeEx. 0 56 17 15 9 2 0.25 0.2 0.12 Ex. 1 16 57.5 15 8.85 2.65 0.25 0.20.01 Ex. 2 67.65 18.82 0 10.41 3.12 0.25 0.2 0.01 Ex. 3 68.5 0 17.8510.5 3.54 0.25 0.2 0.01 Ex. 4 0 37.65 35.3 20.82 6.23 0.25 0.2 0.01 Ex.5 63.1 17.55 16.46 0 2.91 0.25 0.2 0.01 Ex. 6 59.06 16.43 15.41 9.1 00.25 0.2 0.01 Ex. 7 52.5 16 11 7 2 0.25 0.2 0.06 Ex. 8 54.5 17 12 7.52.5 0.25 0.2 0.06 Ex. 9 56.5 18 13 8 3 0.25 0.2 0.06 Ex. 10 58.5 19 148.5 3.5 0.25 0.2 0.06

Example 5 Analyses and Characterization of Ophthalmic Co-PolymericComposition

The resulting lens products, prepared according to the procedurepresented hereinabove, were tested for a series of characteristics, andanalyzed according to industry-accepted parameters, as presented herein.

Following are the quality test results obtained for exemplarycomposition Ex. 0 prepared as described in Example 1 hereinabove:

Refractive index: 1.525;

Loop pull Force (mechanical strength): 45 grams;

Glass transition temperature (Tg): 9° C.;

Shore A hardness: 78;

Visible light transmission: more than 98%;

Unfolding time at 25° C. in 0.9% saline: 5 Seconds;

Visual glistening test: Substantially free of glistening and vacuoles;

Percent extractables/leachables: 0.3%

Resulting dioptric power versus expected resultant power: 20D versus20D;

Tack after EB treatment: tack free; and

Modular transfer function: 0.68.

The characteristics obtained from the aforementioned tests, forexemplary polymeric compositions according to some embodiments of thepresent invention, and lenses made therefrom, produced as describedhereinabove from the aforementioned exemplary polymeric compositionspresented in Example 4, Table 1, are presented in Table 2 below.

The test denoted “1” presents the refractive index as measured at 25°C.;

The test denoted “2” presents the vacuoles presence as measured in waterat 25° C.;

The test denoted “3” presents the Shore A hardness ratios;

The test denoted “4” presents the visible light transmission, given apositive score when accomplishing less than 1% transmission of visiblelight at 370 nm, more than 70% transmission at 400 nm, and a 10% cut-offin the wavelength range of 370-380 nm;

The test denoted “5” presents the unfolding time at 25° C. in normalsaline through sub 2 mm cartridge;

The test denoted “6” presents the halo's test (internal reflection)results in dry conditions, given a positive score if no internalreflection can be detected;

The test denoted “7” presents the percent of detectable leachables afterpost-molding operation; and

The test denoted “8” presents the tack feel, given a positive score ifno tackiness can be perceived.

TABLE 2 TEST No. 1 2 3 4 5 6 7 8 Ex. 0 1.525 clear 78 + 5 + 0.3 + Ex. 11.5371 clear 76.8 + 2 − 0.62 − Ex. 2 1.5466 opaque 81.7 + 6 + 0.78 − Ex.3 1.5354 hazy 81.8 + 2 + 0.59 − Ex. 4 1.5069 opaque 85.8 + 2 + 0.47 +Ex. 5 1.5328 opaque 81.3 + 3 + 0.65 − Ex. 6 1.5265 translucent 74.8 +9 + 1.3 −/+ Ex. 7 1.52 clear 80 + 5.14 + 0.42 −/+ Ex. 8 1.522 clear79.7 + 5.6 + 0.48 −/+ Ex. 9 1.525 clear 78.6 + 4.8 + 0.49 −/+ Ex. 101.527 clear 78 + 4.4 + 0.47 −/+

As can be seen in Table 2, the results obtained for the exemplarypolymeric compositions according to some embodiments of the presentinvention, clearly show superior characteristics by industry standards,wherein the polymeric compositions denoted Ex. 0 and 7-10 exhibitoptimal performance.

Example 6 Curcumin Sample Preparation

Materials and Experimental Methods:

Silica Gel 60 aluminum plates, and preparative Silica gel 60 extra purefor column chromatography 0.063-0.200 mm (70-230 mesh), were obtainedfrom Merck KGaA, Germany.

A commercially available mixture of curcuminoids (Sigma Aldrich, India;Product number C1386; 70% curcumin purity) was post purified to at least97% curcumin as follows. Preparative silica gel was used to fill aprefabricated column, and a mixture of curcuminoids (1% concentration inacetone) was loaded and eluted through the column at 25° C. using amixture of chloroform and ethyl acetate (9:1 ratio).

The solvent was removed by vacuum distillation to afford a residue. Thesolid residue was dried in a vacuum oven at 50° C. under 0.1 mbar for 3hours.

Assay and purity of curcumin was conducted by measuring melting pointand λmax on UV-Vis spectrophotometer. The melting point of the solidresidue was measured at 181° C. (published meting point for curcumin is182-183° C.), and the λmax was found to be 419 nm (within range 415-420nm as the published λmax for curcumin at concentration of 10 mg/l inacetone).

FIG. 1 presents the UV-Vis absorption spectra of the sample of curcuminafter purification on a preparative silica gel column at 25° C. using amixture of chloroform and ethyl acetate (9:1 ratio).

The impurities may be attributed to monodemethoxycurcumin, andbisdemethoxycurcumin, whose boiling point and color differssignificantly from curcumin (reported boiling point ofbisdemethoxycurcumin is 232-233° C.).

Example 7 Transparent Polymeric Object Containing Curcumin

Materials and Experimental Methods:

Dilauroyl peroxide (Cat. No. 34974) was obtained from Acros Organics.

4-[(E)-phenyldiazenyl]phenyl-2-methacrylate (PDPMA) was obtained fromlocal contract laboratories.

The acrylic monomers 2-Phenoxy ethyl methacrylate (POEMA) was obtainedfrom Sartomer Company Inc., Singapore), cyclohexyl acrylate (CHMA) wasobtained from Polysciences Inc., USA) and 1,4-butane diol diacrylate(BDDA) was obtained from Sartomer Company Inc., Singapore).

The separated curcumin from the preparative column chromatographyprocedure described above was weighed into a plastic vial. A solution ofmonomers containing 65.2% 2-phenoxy ethyl methacrylate (POEMA), 32.8%cyclohexyl acrylate (CHMA) and 2% 1,4-butane diol diacrylate (BDDA) byweight percentages respectively, was prepared and added to thecurcumin-containing vial so as to give a curcumin concentration ofapproximately 0.1%. After dissolving the curcumin into thePOEMA/CHMA/BDDA monomer solution, a catalytic amount (0.3%) of dilauroylperoxide was added to the solution as a polymerization initiator.

Rod-shaped objects of 14 mm in diameter and of 100 mm in length wereprepared from the polymeric mixture by placing the curcumin/monomersolution in vials and pressure fitting the closure by keeping the ‘He’jacket over it. Polymerization was effected by placing the vials into40° C. oven and curing for 24 hours. The temperature of the oven wasraised to 60° C. and the vials were heated for 3 hours to effect thepost cure of the rod stock. Circular slices were cut from the rods andsubjected to Soxhlet extraction for 3 hours in toluene.

Thereafter the extracted material samples were dried in air followed bydrying at about 50° C. under vacuum. The UV/Vis transmission andabsorption spectra was measured for the sample slices before and afterthe Soxhlet extraction and drying.

Extraction is a typical step in IOL manufacturing processes, wherein thematrix is swelled with water to a certain limit (typically lower than30% by weight) and the extractables are removed by various solvents.Curcuminoid compounds, according to some embodiments of the presentinvention, are entrapped in the matrix, however, their interaction withacrylic matrix is such that they do not leave the matrix even underextraction conditions.

FIGS. 2A-B present the UV/Vis transmission and absorption spectra asmeasured from slice samples of the rod-shaped object prepared from thecurcumin/POEMA/CHMA/BDDA polymerization mixture, an exemplarycomposition according to some embodiments of the present invention,after mild washing and drying (FIG. 2A) and after Soxhlet extraction for3 hours in toluene (FIG. 2B).

As can be seen in FIGS. 2A-B, the spectra shows that UV light is blockedand the sample does not transmit UV light in a range of about 180 nm to380 nm. As can further be seen in FIGS. 2A-B, the UV/VIS transmissionand absorption spectra of the samples before and after Soxhletextraction is remarkably similar, indicating no measurable leakage ofcurcumin from the sample during extraction.

These results affirm that curcumin is an effective UV stabilizingcompound in a polymeric matrix. UVB and UVC light rays are substantiallyblocked up to 390 nm with transmittance of less than 50% (λ=392.5 nm; %T=49.65%) with about 0.025 percent by weight of curcumin from the totalweight of the sample. The comparative spectra before and after Soxhletextraction affirm that curcumin is an effective UV stabilizer as anentrapped species in an acrylic matrix, exhibiting no tendency ofleaching out of the acrylic matrix even when it is subjected to theexhaustive extraction (transmittance at λ=378.5 nm is 45.918% beforeextraction, and 43.825% after extraction).

Example 8 UV-Blocking Strength Comparison

In order to evaluate the UV/Vis interaction attributes of thecurcumin-doped transparent object, prepared as described hereinabove,these properties were compared with those obtained from a transparentobject prepared with 4-[(E)-phenyldiazenyl]phenyl-2-methacrylate(PDPMA), a commercially available diphenyl azo compound. Curcumin andPDPMA were used at a concentration of 0.005 wt % and 0.25 wt %respectively.

A solution of monomers containing 65.2% POEMA, 32.8% CHMA and 2% BDDA(1,4-butane diol diacrylate) by weight respectively, was mixed to givethe aforementioned test compound concentration. Thereafter, dilauroylperoxide (0.3%) was added as a polymerization initiator.

Rod-shaped objects having 14 mm in diameter and of 100 mm in length wereprepared as described hereinabove. Circular slices were cut from therods and Soxhlet-extracted for 3 hours in toluene. Following theextraction, the material samples were dried in air followed by drying atabout 50° C. under vacuum.

The dye's strength can be assessed by comparing transmittance values atvarious wavelengths in the visible blue light region of 400-500 nm(unlike curcumin, no commercially available synthetic yellow dye absorbsin UV region).

FIGS. 3A-D present the UV/Vis transmission and absorption spectra,measured after Soxhlet extraction and drying, obtained from transparentslices having curcumin at a final content of 0.005 weight percents (FIG.3A), PDPMA at a final content of 0.005 weight percents (FIG. 3B),curcumin at a final content of 0.025 weight percents (FIG. 3C), andPDPMA at a final content of 0.025 weight percents (FIG. 3D).

As can be seen in FIGS. 3A-D, the UV-blocking strength of thetransparent slices having curcumin as a UV-blocker additive, asestimated and compared by their transmission values at wavelengths inthe visible blue light region (400-500 nm), are far more intensive thanthose having PDPMA. Specifically, transmittance at λ=430 nm is about 60%FIG. 3C, about 85% in FIG. 3D, indicating more synthetic dye amount isneeded to partly block the visible blue light.

Hence, curcumin is a yellow dye exhibiting dual function by acting as aUV absorber and visible blue light blocker.

Example 9 UV-Blocker Strength Stability

Lens of 20 diopter with center thickness of 0.75 mm, optic diameter of 6mm and an overall length of 12.5 mm were prepared from a solution ofmonomers containing 65.2% POEMA, 32.8% CHMA and 2% BDDA (1,4-butane dioldiacrylate) by weight.

The tested curcuminoid compound was added to the monomers mixture to afinal concentration of 0.025% w/w and 0.05% w/w, and thereafterdilauroyl peroxide (0.3%) was added as a polymerization initiator.

This pre-polymerization mixture was loaded into two PP mold halves andcured in an oven at 80° C. for 26 hours. Thereafter the molds were keptin a vacuum oven at 110° C. for 3 hours.

After curing, the cast product in the form of a thin circular disc wasmilled to the above mentioned dimensions and subjected to extractiontreatment.

The amount of absorbance between 280-500 nm lost after Soxhletextraction was used as an indication of the amount of curcumin removedfrom the lens material by the Soxhlet extraction process.

FIGS. 4A-D present the UV/Vis absorption spectra, as collected from lensbefore extraction prepared with curcumin at 0.025 weight percentage(FIG. 4A), from the same lens after extraction (FIG. 4B), from lensbefore extraction prepared with curcumin at 0.05 weight percentage (FIG.4C), and from the latter lens after extraction (FIG. 4D).

As can be seen in FIGS. 4A-D, the low decrease in absorbance atwavelength range between 280 nm to 500 nm indicated that very smallamount of curcumin leach out of the lens during exhaustive solventextraction. Apart from UV blocking, it is evident that curcumin remainsentrapped in the acrylic matrix in spite of subjecting the lens tointense extracting conditions.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

What is claimed is:
 1. A co-polymeric composition comprising a polymericbackbone composed of a plurality of backbone units covalently linked toone another, said backbone units being derived from a pre-polymerizationmixture of monomers which comprises: a first aromatic acrylate monomer,characterized as forming a first homopolymer having a refractive indexthat ranges from 1.50 to 1.53; a second aromatic acrylate monomer,characterized as forming a second homopolymer having a Tg lower by arange of 2° C. to 15° C. than a Tg of said first homopolymer; a thirdmonomer, characterized as forming a third homopolymer having a Tg thatranges from 10 to 35° C.; a fourth monomer, characterized as forming afourth homopolymer which is capable of absorbing water to at least 30%of the total weight of said fourth homopolymer; and a fifth monomer,being a crosslinking monomer, wherein: a concentration of said firstaromatic acrylate monomer ranges from 50% to 60% of the total weight ofthe composition; a concentration of said second aromatic acrylatemonomer ranges from 15% to 20% of the total weight of the composition; aconcentration of said third monomer ranges from 10% to 15% of the totalweight of the composition; a concentration of said fourth monomer rangesfrom 5% to 10% of the total weight of the composition; a concentrationof said fifth monomer ranges from 2% to 5% of the total weight of thecomposition; and the composition is being formulated for ophthalmicapplication and characterized by at least one of: a glass transitiontemperature not higher than 15° C.; a loop pull force mechanicalstrength of at least 40 grams; a Shore A hardness that ranges from 77 to80; and an unfolding time of less than 6 seconds.
 2. The composition ofclaim 1, wherein said first aromatic monomer is selected from the groupconsisting of 2-phenoxyethyl acrylate, 2-phenoxy ethyl methacrylate,2-benzyloxy ethyl acrylate, 2-benzyloxy ethyl methacrylate andcombinations thereof.
 3. The composition of claim 1, wherein said secondaromatic monomer is selected from the group consisting of 2-phenylethylacrylate, benzyl acrylate, cyclohexyl acrylate, 2-chlorophenyl acrylate,4-methyl benzyl acrylate, 2,4,6-tribromophenyl acrylate,pentabromophenyl acrylate and any combinations thereof.
 4. Thecomposition of claim 1, wherein said third monomer is selected from thegroup consisting of cellosolve methacrylate, methoxy ethyl acrylate,polyethylene glycol monomethacrylate, 1-dihydroxyperflurobutylmethacrylate, 2,5-dibromopropyl methacrylate, hexyl methacrylate,glycerol monomethacrylate, trifluroethyl methacrylate, butylmethacrylate, n-ocyl/isooctyl methacrylate, n-decyl/isodecylmethacrylate, ethyl methacrylate, ethylene triglycol methacrylate, butyldiglycol methacrylate, methoxy polyethylene glycol 350 methhacrylate,methoxy polyethylene glycol 500 methhacrylate, methoxy polyethyleneglycol 1000 methhacrylate, methoxy polyethylene glycol 2000methhacrylate, methoxy polyethylene glycol 5000 methhacrylate,polypropylene glycon methacrylate, ethoxytriglycol methacrylate,2-ethoxyethoxy ethyl methacrylate, methoxy triethyleglycol methacrylate,phenoxy polyethylene glycol monomethacrylate and any combinationsthereof.
 5. The composition of claim 1, wherein said forth monomer isselected from the group consisting of hydroxyl ethyl methacrylate,glycerol monomethacrylate, ethylene triglycol methacrylate, butyldiglycol methacrylate, methoxy polyethylene glycol 350 methhacrylate,methoxy polyethylene glycol 500 methhacrylate, methoxy polyethyleneglycol 1000 methhacrylate, methoxy polyethylene glycol 2000methhacrylate, methoxy polyethylene glycol 5000 methhacrylate,polypropylene glycon methacrylate, ethoxytriglycol methacrylate, methoxytriethyleglycol methacrylate, phenoxy polyethylene glycolmonomethacrylate and any combinations thereof.
 6. The composition ofclaim 1, wherein said fifth monomer is selected from the groupconsisting of ethylene glycol dimethacrylate, 1,4-butane dioldiacrylate, glycerol dimethacrylate, allyl methacrylate, 1,6 heaxanediol diacrylate, 1,4-butanediol dimethacrylate, 1,6-hexane dioldimethacrylate and any combinations thereof.
 7. The composition of claim1, wherein said mixture further comprises a curing agent selected fromthe group consisting of a peroxy catalyst, an oxide catalysts,tert-butyl peroxy-2-ethylhexanoate,2,4,6-trimethylbenzoyldiphenylphosphine oxide and any combinationsthereof.
 8. The composition of claim 1, further comprising anultraviolet absorbing compound selected from the group consisting of abenzophenone, 2-hydroxybenzophenone, 2-(2-hydroxyphenyl)benzotriazole,2-acryloxyethoxy hydroxyl benzophenone,phenol-2-(5-chloro-2H-benozotriazol-2-yl)-6-(1,1-)dimethyl-4-methyl,4-benzoyl-3-hydroxyphenyl-2-methacrylate,2-[4-(2h-1,2,3-benzotriazol2-yl)-3-hydroxyphenoxy]ethyl-2-methacrylateand any combinations thereof.
 9. The composition of claim 1, furthercomprising at least one curcuminoid compound incorporated therein orthereon said curcuminoid compound is selected from the group consistingof curcumin, bisdemethoxycurcumin, monodemethoxycurcumin andtetrahydroxycurcumin.
 10. A co-polymeric composition comprising apolymeric backbone composed of a plurality of backbone units covalentlylinked to one another and a curcuminoid compound incorporated in or onthe composition, said backbone units being derived from apre-polymerization mixture of monomers which comprises: a first aromaticacrylate monomer, characterized as forming a first homopolymer having arefractive index that ranges from 1.50 to 1.53; a second aromaticacrylate monomer, characterized as forming a second homopolymer having aTg lower by a range of 2° C. to 30° C. than a Tg of said firsthomopolymer; a third monomer, characterized as forming a thirdhomopolymer having a Tg lower than 35° C.; a fourth monomer,characterized as forming a fourth homopolymer which is capable ofabsorbing water to at least 20% of the total weight of said fourthhomopolymer; and a fifth monomer, being a crosslinking monomer, wherein:a concentration of said first aromatic acrylate monomer ranges from 50%to 60% of the total weight of the composition; a concentration of saidsecond aromatic acrylate monomer ranges from 15% to 20% of the totalweight of the composition; a concentration of said third monomer rangesfrom 10% to 15% of the total weight of the composition; a concentrationof said fourth monomer ranges from 5% to 10% of the total weight of thecomposition; a concentration of said fifth monomer ranges from 2% to 5%of the total weight of the composition; and the composition isformulated for ophthalmic application and characterized by at least oneof: a glass transition temperature not higher than 15° C.; a loop pullforce mechanical strength of at least 40 grams; a Shore A hardness thatranges from 77 to 80; and an unfolding time of less than 6 seconds. 11.The composition of claim 10, having a visible light transmission of atleast 95% of incident visible light.
 12. The composition of claim 10,having a refractive index of at least 1.53.
 13. The composition of claim10, having loop pull force mechanical strength of at least 40 grams. 14.The composition of claim 10, having an unfolding time of less than 6seconds.
 15. The composition of claim 10, having a leachable content ofless than 0.6%.
 16. An ophthalmic or ocular device, comprising thecomposition of claim
 10. 17. The device of claim 16, selected from thegroup consisting of an intraocular lens (IOL), a contact lens, animplantable ocular device, a keratoprosthesis, a phakic lens, an aphakiclens, a corneal ring, a capsular bag extension ring, a corneal inlay anda corneal onlay.
 18. The composition of claim 10, further characterizedby at least one of: a visible light transmission of at least 97% ofincident visible light; and a refractive index of at least 1.53.
 19. Anophthalmic or ocular device, comprising the composition of claim
 1. 20.The ophthalmic or ocular device of claim 19, selected from the groupconsisting of an intraocular lens (IOL), a contact lens, an implantableocular device, a keratoprosthesis, a phakic lens, an aphakic lens, acorneal ring, a capsular bag extension ring, a corneal inlay and acorneal onlay.